Materiały źródłowe

• #1 Pre-eclampsia: its pathogenesis and pathophysiolgy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4928171/

  Pre-eclampsia is a pregnancy-specific disorder that has a worldwide prevalence of 58%. […] Recently it has been postulated that it is a two-stage disease with an imbalance between angiogenic and anti-antigenic factors. […] The central hypothesis is that pre-eclampsia results from defective spiral artery remodelling, leading to cellular ischaemia in the placenta, which in turn results in an imbalance between anti-angiogenic and pro-angiogenic factors. […] The main pathological feature of early-onset PE is incomplete transformation of the spiral arteries, resulting in hypoperfusion of the placenta and reduced nutrient supply to the foetus. […] In PE, it has almost been established that there is reduced blood flow to the placenta, especially in the early-onset type, because of defective spiral artery remodelling and acute artherosis.

• #2 Pre-eclampsia: its pathogenesis and pathophysiolgy – ScienceOpen

  https://www.scienceopen.com/document?vid=c4ce090e-73df-46f5-abc7-feae72194c2d

  Pre-eclampsia is a pregnancy-specific disorder that has a worldwide prevalence of 5–8%. It is one of the main causes of maternal and perinatal morbidity and mortality globally and accounts for 50 000–60 00 deaths annually, with a predominance in the low- and middle-income countries. […] Recently it has been postulated that it is a two-stage disease with an imbalance between angiogenic and anti-antigenic factors. This review covers the latest thoughts on the pathogenesis and pathology of pre-eclampsia. The central hypothesis is that pre-eclampsia results from defective spiral artery remodelling, leading to cellular ischaemia in the placenta, which in turn results in an imbalance between anti-angiogenic and pro-angiogenic factors. This imbalance in favour of anti-angiogenic factors leads to widespread endothelial dysfunction, affecting all the maternal organ systems. In addition, there is foetal growth restriction (FGR). The exact aetiology remains elusive.

• #3 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. […] The past two decades have seen major advances in the field of pre-eclampsia, although the underlying pathogenesis remains elusive. Currently, the disease can be understood in terms of both placental and maternal dysfunction. Various genetic, angiogenic, structural and metabolic pathways have been implicated in pre-eclampsia, including spiral artery remodelling, placental oxygenation, redox and immune tolerance at the maternalfetal interface and the balance of angiogenic and antiangiogenic factors. In particular, certain antiangiogenic proteins have emerged as key pathogenic mediators of the maternal disease, and their discovery has provided opportunities for the development of novel diagnostics such as risk calculators, prediction models and triage tools.

• #4 Pathophysiology of Pre-Eclampsia—Two Theories of the Development of the Disease

  https://www.mdpi.com/1422-0067/25/1/307

  Pre-eclampsia (PE) continues to be a leading cause of maternal and fetal mortality and morbidity. While substantial progress has been made in understanding the pathomechanisms of PE, the pathophysiology of the disease is still not fully understood. While the “two-stage model” of the development of PE is the most widely accepted theory, stating that the placenta is the main source of the disease, there are some other pathophysiological models of PE. […] The prevailing and most plausible theory regarding the development of PE is the two-stage theory. In this model, the first stage of the disease involves impaired placentation and reduced placental perfusion, while the second stage encompasses general maternal endothelial damage and dysfunction. […] According to this theory, the initial reduction in placental perfusion is mainly caused by disruptions in the process of placental development, known as placentation. This disturbance arises from impaired trophoblast invasion into the spiral arteries during the first half of pregnancy.

• #5 Modern concepts of etiology, pathogenesis and risk factors for preeclampsia – Abramova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/77046/en_US

  Preeclampsia is a serious complication of pregnancy and complicates its course in 2-8% of all cases. […] Of particular interest is the study of the molecular mechanisms of etiopathogenesis and risk factors for preeclampsia, which, unfortunately, are currently poorly studied and understood, thus dictating the need for further study of this complication of pregnancy. This article discusses the current understanding of the etiology, pathogenesis and risk factors for preeclampsia. […] The mechanisms of PE occurrence are extensively studied worldwide, and 30 hypotheses for the development of this pregnancy complication were reported, most of which placentation disorders are the most significant. […] The two-stage model of PE development that was introduced by Redman in 1991 is currently generally accepted. At stage 1 of PE, abnormal placentation occurs in early pregnancy, which leads to disseminated endothelial dysfunction and maternal syndrome at stage 2.

• #6 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  The pathogenesis of pre-eclampsia can be considered to involve two stages: abnormal placentation and the development of the maternal syndrome. Genetic factors, maternal factors and immunological factors may cause placental dysfunction (stage I), which in turn leads to the release of antiangiogenic factors (such as soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin (sENG)) and other inflammatory mediators that induce preeclampsia (stage II). […] Pre-eclampsia is understood to originate in the placenta, and its initial stages can be understood as the placental syndrome. The presence of the placenta, as opposed to the fetus, is essential to the development of pre-eclampsia, which is evident by the development of the condition in hydatidiform mole. […] The characteristics of pre-eclamptic placenta have been studied for well over a century.

• #7 An Update Review of the Pathogenesis Hypothesis in Preeclampsia

  https://www.imrpress.com/journal/CEOG/49/8/10.31083/j.ceog4908170/htm

  At present, the pathogenesis of preeclampsia is still unclear, we wrote this article to make a uptodate review of this disease. […] At present, the pathogenesis of preeclampsia is still unclear, large number of hypothesis have been proposed for the placental dysfunction, including oxidative stress, abnormal natural killer cells at the maternal-fetal interface, and genetic and environmental factors, though none have conclusive evidence in humans. […] Preeclampsia progresses in 2 stages: in the first stage, uterine spiral artery remodeling disordered, resulting in abnormal trophoblastic infiltration and superficial placenta implantation in the maternal myometrium. In the second stage, some maternal syndrome appears, which is associated with the systemic inflammatory response caused by the placenta, leading to the signs of preeclampsia.

• #8 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  The pathogenesis of pre-eclampsia can be considered to involve two stages: abnormal placentation and the development of the maternal syndrome. Genetic factors, maternal factors and immunological factors may cause placental dysfunction (stage I), which in turn leads to the release of antiangiogenic factors (such as soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin (sENG)) and other inflammatory mediators that induce preeclampsia (stage II). […] Pre-eclampsia is understood to originate in the placenta, and its initial stages can be understood as the placental syndrome. The presence of the placenta, as opposed to the fetus, is essential to the development of pre-eclampsia, which is evident by the development of the condition in hydatidiform mole. […] The characteristics of pre-eclamptic placenta have been studied for well over a century.

• #9 Pre-eclampsia – Wikipedia

  https://en.wikipedia.org/wiki/Pre-eclampsia

  Pre-eclampsia is thought to result from an abnormal placenta, the removal of which ends the disease in most cases. […] Abnormal development of the placenta leads to poor placental perfusion. The placenta of women with pre-eclampsia is abnormal and characterized by poor trophoblastic invasion. […] It is thought that this results in oxidative stress, hypoxia, and the release of factors that promote endothelial dysfunction, inflammation, and other possible reactions. […] The clinical manifestations of pre-eclampsia are associated with general endothelial dysfunction, including vasoconstriction and end-organ ischemia. […] Implicit in this generalized endothelial dysfunction may be an imbalance of angiogenic and anti-angiogenic factors. […] Both circulating and placental levels of soluble fms-like tyrosine kinase-1 (sFlt-1) are higher in women with pre-eclampsia than in women with normal pregnancy.

• #10 Eclampsia – Wikipedia

  https://en.wikipedia.org/wiki/Eclampsia

  Pre-eclampsia is a hypertensive disorder of pregnancy that presents with three main features: new onset of high blood pressure, large amounts of protein in the urine or other organ dysfunction, and edema. […] The mechanisms of eclampsia and preeclampsia are not definitively understood, but following provides some insight. The presence of a placenta is required, and eclampsia resolves if it is removed. […] Reduced blood flow to the placenta (placental hypoperfusion) may be a key feature of the process. It is typically accompanied by increased sensitivity of the maternal vasculature to agents which cause constriction of the small arteries, leading to reduced blood flow to multiple organs. […] The pathogenesis of pre-eclampsia is poorly understood and may be attributed to factors related to the pregnant person and placenta since pre-eclampsia is seen in molar pregnancies absent of a fetus or fetal tissue. […] Eclampsia is associated with hypertensive encephalopathy in which cerebral vascular resistance is reduced, leading to increased blood flow to the brain, cerebral edema and resultant convulsions.

• #11 Pre-eclampsia: its pathogenesis and pathophysiolgy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4928171/

  Pre-eclampsia is a pregnancy-specific disorder that has a worldwide prevalence of 58%. […] Recently it has been postulated that it is a two-stage disease with an imbalance between angiogenic and anti-antigenic factors. […] The central hypothesis is that pre-eclampsia results from defective spiral artery remodelling, leading to cellular ischaemia in the placenta, which in turn results in an imbalance between anti-angiogenic and pro-angiogenic factors. […] The main pathological feature of early-onset PE is incomplete transformation of the spiral arteries, resulting in hypoperfusion of the placenta and reduced nutrient supply to the foetus. […] In PE, it has almost been established that there is reduced blood flow to the placenta, especially in the early-onset type, because of defective spiral artery remodelling and acute artherosis.

• #12 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  The endothelial cell dysfunction that is characteristic of preeclampsia may be partially due to an extreme activation of leukocytes in the maternal circulation, as evidenced by an upregulation of type 1 helper T cells. […] Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with preeclampsia syndrome. In fact, studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. This is because the placental hypoperfusion resulting from the incomplete invasion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.

• #13 Hypertensive Disorders of Pregnancy – OpenAnesthesia

  https://www.openanesthesia.org/keywords/hypertensive-disorders-of-pregnancy/

  The pathogenesis of preeclampsia is abnormal placentation due to impaired angiogenesis of spiral arteries (terminal branches of the uterine artery), leading to placental ischemia and release of antiangiogenic factors to maternal circulation, leading to systemic endothelial dysfunction. […] During normal placental development, fetal cytotrophoblasts invade the maternal spiral arteries, converting them into large caliber capacitance vessels capable of providing adequate placental perfusion to sustain fetal growth. […] In preeclampsia, the fetal cytotrophoblasts fail to differentiate into the invasive endothelial phenotype. […] The end result is a shallow invasion of the maternal spiral arteries, which remain small-caliber, high-resistance vessels. […] This results in relative placental under perfusion, hypoxia, oxidative stress, and release of antiangiogenic factors into the maternal circulation, causing widespread systemic maternal endothelial dysfunction.

• #14 Hypertensive Disorders of Pregnancy – OpenAnesthesia

  https://www.openanesthesia.org/keywords/hypertensive-disorders-of-pregnancy/

  The pathogenesis of preeclampsia is abnormal placentation due to impaired angiogenesis of spiral arteries (terminal branches of the uterine artery), leading to placental ischemia and release of antiangiogenic factors to maternal circulation, leading to systemic endothelial dysfunction. […] During normal placental development, fetal cytotrophoblasts invade the maternal spiral arteries, converting them into large caliber capacitance vessels capable of providing adequate placental perfusion to sustain fetal growth. […] In preeclampsia, the fetal cytotrophoblasts fail to differentiate into the invasive endothelial phenotype. […] The end result is a shallow invasion of the maternal spiral arteries, which remain small-caliber, high-resistance vessels. […] This results in relative placental under perfusion, hypoxia, oxidative stress, and release of antiangiogenic factors into the maternal circulation, causing widespread systemic maternal endothelial dysfunction.

• #15 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  The endothelial cell dysfunction that is characteristic of preeclampsia may be partially due to an extreme activation of leukocytes in the maternal circulation, as evidenced by an upregulation of type 1 helper T cells. […] Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with preeclampsia syndrome. In fact, studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. This is because the placental hypoperfusion resulting from the incomplete invasion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.

• #16 Hypertensive Disorders of Pregnancy – OpenAnesthesia

  https://www.openanesthesia.org/keywords/hypertensive-disorders-of-pregnancy/

  The pathogenesis of preeclampsia is abnormal placentation due to impaired angiogenesis of spiral arteries (terminal branches of the uterine artery), leading to placental ischemia and release of antiangiogenic factors to maternal circulation, leading to systemic endothelial dysfunction. […] During normal placental development, fetal cytotrophoblasts invade the maternal spiral arteries, converting them into large caliber capacitance vessels capable of providing adequate placental perfusion to sustain fetal growth. […] In preeclampsia, the fetal cytotrophoblasts fail to differentiate into the invasive endothelial phenotype. […] The end result is a shallow invasion of the maternal spiral arteries, which remain small-caliber, high-resistance vessels. […] This results in relative placental under perfusion, hypoxia, oxidative stress, and release of antiangiogenic factors into the maternal circulation, causing widespread systemic maternal endothelial dysfunction.

• #17 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  The endothelial cell dysfunction that is characteristic of preeclampsia may be partially due to an extreme activation of leukocytes in the maternal circulation, as evidenced by an upregulation of type 1 helper T cells. […] Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with preeclampsia syndrome. In fact, studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. This is because the placental hypoperfusion resulting from the incomplete invasion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.

• #18 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  Molecular mechanisms that mediate spiral artery remodelling are still being debated. […] Thus, the concept of defective placentation and failure to transform uterine spiral arteries has emerged as central to the pathogenesis of pre-eclampsia. […] Oxidative stress also occurs at the maternalfetal interface and is thought to have a key role in normal and defective placental development. […] The concept of a maternal predisposition to pre-eclampsia has been posited and supported by extensive work done at the vascular level of affected mothers. […] The hallmarks of pre-eclampsia are not confined to the placenta but also extend to widespread effects in the mother that can be collectively viewed as the maternal syndrome. […] Experimental and epidemiological studies support a pathological role for imbalance in circulating angiogenic factors in the aetiology of the maternal syndrome. Excess levels of the antiangiogenic factor sFLT1, which is produced in the placenta and released into the maternal circulation, induce maternal endothelial dysfunction leading to preeclamptic signs and symptoms. […] High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials.

• #19 Pre-eclampsia: its pathogenesis and pathophysiolgy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4928171/

  The exact mechanism for this is not known but various factors, such as abnormal genetic variations, biology of the trophoblasts or defective trophoblast differentiation acting together with extrinsic factors, such as maternal constitutional factors, action of macrophage defense mechanisms, impaired action of dNK cells and maternal endothelial cells have been advanced. […] It is therefore believed that placental ischaemiareperfusion injury is central to the development of PE. […] There is increasing evidence that suggests an imbalance between pro-angiogenic and anti-angiogenic factors are responsible for the pathophysiological effects seen in PE, and these appear before clinical signs are apparent. […] The disproportionate levels of anti-angiogenic factors such as sEng and sFlt-1, and pro-angiogenic factors such as VEGF, PlGF and TGF, are believed to cause generalised maternal endothelial dysfunctions, leading to hypertension, renal endotheliosis and blood coagulation.

• #20 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. […] In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. […] We discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. […] Pre-eclampsia is characterized by defective placentation, placental ischaemia, abnormal spiral artery remodelling, oxidative stress at the maternal-fetal interface and angiogenic imbalance in the maternal circulation with ensuing endothelial and end-organ damage.

• #21

  https://www.openaccessjournals.com/articles/pathophysiologyof-hypertension-inpreeclampsia.html

  Hypertensive disorders in pregnancy, including preeclampsia, are the second largest contributor to maternal mortality worldwide. Despite the seriousness of the disease the pathophysiology of preeclampsia remains poorly understood. […] While it is widely accepted that the pathophysiology of preeclampsia begins with abnormal placentation, it remains a poorly understood multisystem disease. The means by which abnormal placentation results in systemic dysfunction is an area of ongoing research. […] In preeclampsia, due to abnormal cytotrophoblast invasion and deficient spiral artery remodeling this low resistance vasculature does not form, which results in decreased blood flow to the placenta. This placental ischemia appears to play an overarching role in the development of preeclampsia. […] Preeclampsia can therefore be thought of as a multistep disease process. In the first stage, abnormal placentation and deficient spiral artery remodeling leads to placental ischemia. Placental ischemia in turn leads to the clinical manifestations of preeclampsia, including the development of hypertension and proteinuria.

• #22 Pre-eclampsia: its pathogenesis and pathophysiolgy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4928171/

  The exact mechanism for this is not known but various factors, such as abnormal genetic variations, biology of the trophoblasts or defective trophoblast differentiation acting together with extrinsic factors, such as maternal constitutional factors, action of macrophage defense mechanisms, impaired action of dNK cells and maternal endothelial cells have been advanced. […] It is therefore believed that placental ischaemiareperfusion injury is central to the development of PE. […] There is increasing evidence that suggests an imbalance between pro-angiogenic and anti-angiogenic factors are responsible for the pathophysiological effects seen in PE, and these appear before clinical signs are apparent. […] The disproportionate levels of anti-angiogenic factors such as sEng and sFlt-1, and pro-angiogenic factors such as VEGF, PlGF and TGF, are believed to cause generalised maternal endothelial dysfunctions, leading to hypertension, renal endotheliosis and blood coagulation.

• #23 Modern concepts of etiology, pathogenesis and risk factors for preeclampsia – Abramova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/77046

  With PE, these processes are disrupted, which ultimately leads to defective trophoblast invasion and impaired formation of uteroplacental blood flow. […] One of the mechanisms that disrupt the invasion processes is the persistent hypoxia-mediated overexpression of HIF-1/HIF-2 and TGF-. […] Oxidative damage to the placenta induces apoptosis processes, such as the release of various antiangiogenic factors, proinflammatory cytokines, and vasoactive compounds into the mothers bloodstream, which develops major systemic endothelial cell dysfunction, accompanied by inflammation and vasoconstriction. […] Endothelial dysfunction is central to the maternal syndrome pathogenesis of PE and underlies the imbalance of vasoactive mediators, which induces a shift toward increased vasoconstrictor production.

• #24 Hypoxia in the pathogenesis of preeclampsia

  https://www.jstage.jst.go.jp/article/jsshp/5/2/5_HRP2017-014/_html/-char/en

  In preeclampsia, ROS are produced in poorly perfused placentas, inducing vasoconstriction and resulting in endothelial dysfunction. […] The site of implantation is known to be hypoxic in early pregnancy. […] Hypoxia is necessary for the invasion of EVTs into the uterine decidua and myometrium. […] HIF-1 is stimulated by oxidative stress and growth factors to induce glycolytic activity. […] HIF-1 is activated under hypoxic conditions and induces the transcription of numerous genes. […] The abnormal protein reaction under hypoxic conditions could contribute to the pathogenesis of preeclampsia. […] HIF is also critical for EVT invasion into the maternal uterine decidua and myometrium during placentation. […] Disturbed placental angiogenesis impairs placental perfusion, leading to the production of abundant soluble vascular endothelial growth factor receptor-1 (sFlt-1) and soluble endoglin (sEng), and reduces the production of placental growth factor (PlGF), which appears in the maternal circulation several weeks before the onset of preeclampsia.

• #25 Hypoxia in the pathogenesis of preeclampsia

  https://www.jstage.jst.go.jp/article/jsshp/5/2/5_HRP2017-014/_html/-char/en

  Oxidative stress is required for the development of hypoxic injury and has been investigated as a key factor in the pathogenesis of preeclampsia. […] In preeclampsia, hypoxia at the implantation site can contribute to lesion formation, leading to poor placentation. […] Increased levels of HIF-1 can induce secretion of soluble vascular endothelial growth factor receptor-1 (sFlt-1), which is known to be a major factor influencing the pathogenesis of preeclampsia. […] The pathophysiology is partly explained as poor placentation, which is caused by impaired trophoblast invasion. […] During the first stage of pathogenesis, extravillous trophoblasts (EVTs) invade the uterine decidua and myometrium, resulting in the remodeling of maternal spiral arteries 2 weeks after implantation. […] Shallow placentation results in unsuccessful vascular transformation, impairing fetal viability and increasing the risk for preeclampsia.

• #26 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  Molecular mechanisms that mediate spiral artery remodelling are still being debated. […] Thus, the concept of defective placentation and failure to transform uterine spiral arteries has emerged as central to the pathogenesis of pre-eclampsia. […] Oxidative stress also occurs at the maternalfetal interface and is thought to have a key role in normal and defective placental development. […] The concept of a maternal predisposition to pre-eclampsia has been posited and supported by extensive work done at the vascular level of affected mothers. […] The hallmarks of pre-eclampsia are not confined to the placenta but also extend to widespread effects in the mother that can be collectively viewed as the maternal syndrome. […] Experimental and epidemiological studies support a pathological role for imbalance in circulating angiogenic factors in the aetiology of the maternal syndrome. Excess levels of the antiangiogenic factor sFLT1, which is produced in the placenta and released into the maternal circulation, induce maternal endothelial dysfunction leading to preeclamptic signs and symptoms. […] High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials.

• #27 Hypoxia in the pathogenesis of preeclampsia

  https://www.jstage.jst.go.jp/article/jsshp/5/2/5_HRP2017-014/_html/-char/en

  In preeclampsia, ROS are produced in poorly perfused placentas, inducing vasoconstriction and resulting in endothelial dysfunction. […] The site of implantation is known to be hypoxic in early pregnancy. […] Hypoxia is necessary for the invasion of EVTs into the uterine decidua and myometrium. […] HIF-1 is stimulated by oxidative stress and growth factors to induce glycolytic activity. […] HIF-1 is activated under hypoxic conditions and induces the transcription of numerous genes. […] The abnormal protein reaction under hypoxic conditions could contribute to the pathogenesis of preeclampsia. […] HIF is also critical for EVT invasion into the maternal uterine decidua and myometrium during placentation. […] Disturbed placental angiogenesis impairs placental perfusion, leading to the production of abundant soluble vascular endothelial growth factor receptor-1 (sFlt-1) and soluble endoglin (sEng), and reduces the production of placental growth factor (PlGF), which appears in the maternal circulation several weeks before the onset of preeclampsia.

• #28 Pre-eclampsia – Wikipedia

  https://en.wikipedia.org/wiki/Pre-eclampsia

  Oxidative stress may also play an important part in the pathogenesis of pre-eclampsia. […] Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. […] It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. […] One hypothesis for vulnerability to pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus. […] In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. […] Immune factors may also play a role.

• #29 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #30 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  Data show that an imbalance of proangiogenic and antiangiogenic factors produced by the placenta may play a major role in mediating endothelial dysfunction. Angiogenesis is critical for successful placentation and the normal interaction between trophoblasts and endothelium. […] Evidence also suggests that oxidative stress, circulatory maladaptation, inflammation, and humoral, mineral, and metabolic abnormalities contribute to the endothelial dysfunction and pathogenesis of preeclampsia.

• #31 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  Molecular mechanisms that mediate spiral artery remodelling are still being debated. […] Thus, the concept of defective placentation and failure to transform uterine spiral arteries has emerged as central to the pathogenesis of pre-eclampsia. […] Oxidative stress also occurs at the maternalfetal interface and is thought to have a key role in normal and defective placental development. […] The concept of a maternal predisposition to pre-eclampsia has been posited and supported by extensive work done at the vascular level of affected mothers. […] The hallmarks of pre-eclampsia are not confined to the placenta but also extend to widespread effects in the mother that can be collectively viewed as the maternal syndrome. […] Experimental and epidemiological studies support a pathological role for imbalance in circulating angiogenic factors in the aetiology of the maternal syndrome. Excess levels of the antiangiogenic factor sFLT1, which is produced in the placenta and released into the maternal circulation, induce maternal endothelial dysfunction leading to preeclamptic signs and symptoms. […] High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials.

• #32 Pathophysiology of Pre-Eclampsia—Two Theories of the Development of the Disease

  https://www.mdpi.com/1422-0067/25/1/307

  The most probable pathophysiological connection between the first stage of PE, characterized by impaired placental perfusion, and the subsequent second stage, marked by maternal endothelial dysfunction, is the increased production of anti-angiogenic factors by poorly perfused placentas in women who later develop PE. […] Maternal endothelial injury and dysfunction are responsible for the manifestation of most clinical symptoms characteristic of PE, including edema, thrombocytopenia, neurological complications, visual disturbances and proteinuria. […] The primary mechanism responsible for endothelial dysfunction in PE appears to be the anti-angiogenic activity of sFlt-1 and sEng, which are overproduced in women who develop PE. […] Although the two-stage model of PE is the most popular theory of the disease, the cardiac origin of PE must also be taken into consideration as a potential pathomechanism. A common element in both theories is impaired placental perfusion.

• #33 Eclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/253960-overview

  In addition, it is believed that antiangiogenic factors, such as placental protein fms-like tyrosine kinase 1 (sFlt-1) and activin A, antagonize vascular endothelial growth factor (VEGF). Elevated levels of these proteins cause a reduction of VEGF and induce systemic and local endothelial cell dysfunction. […] Evidence indicates that leptin molecules increase in the circulation of women with eclampsia, inducing oxidative stress, another factor in eclampsia, on cells. […] The mechanism(s) responsible for the development of eclampsia remain(s) unclear. Genetic predisposition, immunology, endocrinology, nutrition, abnormal trophoblastic invasion, coagulation abnormalities, vascular endothelial damage, cardiovascular maladaptation, dietary deficiencies or excess, and infection have been proposed as etiologic factors for preeclampsia/eclampsia. […] Imbalanced prostanoid production and increased plasma antiphospholipids have also been implicated in eclampsia. In murine models, placental ischemia appears to be associated with an increased susceptibility to seizures and cerebrospinal fluid (CSF) inflammation.

• #34 Endothelial dysfunction in the pathogenesis of pre-eclampsia in Ghanaian women | BMC Physiology | Full Text

  https://bmcphysiol.biomedcentral.com/articles/10.1186/s12899-017-0029-4

  The marked reduction in serum VEGF levels determined in association with pre-eclampsia could be attributed to high soluble fms-like tyrosine kinase-1 (sflt-1) levels. Soluble flt-1 usually binds to and inhibits multiple pro-angiogenic proteins such as VEGF and placental growth factor (PIGF) by preventing their communication with the respective endothelial cell receptors. […] In this study, maternal serum free VEGF levels were found to be markedly lower in the early compared to the late onset PE (p<0.001) buttressing the fact that early onset disease is a severer disease leading to a more pronounced endothelial dysfunction. [...] This strongly suggests that significant decrease in free VEGF levels resulting in endothelial dysfunction is implicated in the pathogenesis of pre-eclampsia.

• #35 Preeclampsia: From Etiopathology to Organ Dysfunction | IntechOpen

  https://www.intechopen.com/chapters/79809

  There is an imbalance of proangiogenic (VEGF) and antiangiogenic (soluble fms-like tyrosine kinase sFlt-I) proteins in placental vascular bed. […] In preeclampsia, sFlt-1 is a soluble antiangiogenic protein that is elevated, which binds and inactivates or reduces biological activity of free-circulating proangiogenic proteins, vascular endothelial growth factor (VEGF), and placental growth factor (PIGF), causing endothelial dysfunction.

• #36 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #37

  https://www.openaccessjournals.com/articles/pathophysiologyof-hypertension-inpreeclampsia.html

  However, the precise cause for both deficient spiral artery remodeling and its effects on the development of hypertension remain unclear. […] Placental ischemia is thought to cause hypoxia-induced release of placental factors, leading to widespread vascular and endothelial dysfunction. Endothelial dysfunction, which is associated with the development of hypertension, occurs due to an imbalance in angiogenic factors. […] Thus angiogenic factors have drawn increasing attention for their role in the pathogenesis of preeclampsia. […] Preeclampsia is characterized by an excess of anti-angiogenic factors with a simultaneous deficiency in pro-angiogenic factors. […] sFlt-1 appears to enact its anti-angiogenic effects through the antagonism of VEGF and PlGF. […] This effect of sFlt-1 is dose-dependent fashion, with a strong correlation of sFlt level and severity of disease.

• #38 Hypoxia in the pathogenesis of preeclampsia

  https://www.jstage.jst.go.jp/article/jsshp/5/2/5_HRP2017-014/_html/-char/en

  In preeclampsia, ROS are produced in poorly perfused placentas, inducing vasoconstriction and resulting in endothelial dysfunction. […] The site of implantation is known to be hypoxic in early pregnancy. […] Hypoxia is necessary for the invasion of EVTs into the uterine decidua and myometrium. […] HIF-1 is stimulated by oxidative stress and growth factors to induce glycolytic activity. […] HIF-1 is activated under hypoxic conditions and induces the transcription of numerous genes. […] The abnormal protein reaction under hypoxic conditions could contribute to the pathogenesis of preeclampsia. […] HIF is also critical for EVT invasion into the maternal uterine decidua and myometrium during placentation. […] Disturbed placental angiogenesis impairs placental perfusion, leading to the production of abundant soluble vascular endothelial growth factor receptor-1 (sFlt-1) and soluble endoglin (sEng), and reduces the production of placental growth factor (PlGF), which appears in the maternal circulation several weeks before the onset of preeclampsia.

• #39 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  Molecular mechanisms that mediate spiral artery remodelling are still being debated. […] Thus, the concept of defective placentation and failure to transform uterine spiral arteries has emerged as central to the pathogenesis of pre-eclampsia. […] Oxidative stress also occurs at the maternalfetal interface and is thought to have a key role in normal and defective placental development. […] The concept of a maternal predisposition to pre-eclampsia has been posited and supported by extensive work done at the vascular level of affected mothers. […] The hallmarks of pre-eclampsia are not confined to the placenta but also extend to widespread effects in the mother that can be collectively viewed as the maternal syndrome. […] Experimental and epidemiological studies support a pathological role for imbalance in circulating angiogenic factors in the aetiology of the maternal syndrome. Excess levels of the antiangiogenic factor sFLT1, which is produced in the placenta and released into the maternal circulation, induce maternal endothelial dysfunction leading to preeclamptic signs and symptoms. […] High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials.

• #40 Preeclampsia: From Etiopathology to Organ Dysfunction | IntechOpen

  https://www.intechopen.com/chapters/79809

  Preeclampsia is a hypertensive disorder of pregnancy causing multi-organ dysfunction syndrome with placental dysfunction occurring in the latter half of pregnancy, with major cause of maternal morbidity, maternal intensive care admissions, Cesarean section, end-organ damage, and fetal complications. […] The pathogenesis includes endothelial activation and dysfunction leading to vasospasm. […] In preeclampsia, inflammatory mediators contributed by systemic oxidative stress are tumor necrosis factor alpha (TNF-Alpha) and interleukins that in turn lead to formation of lipid peroxidases, producing toxic radicals that injure systemic vascular endothelial cells. […] Injury to systemic endothelial cell is crucial in pathogenesis of preeclampsia and likely secretes placental protein factors into maternal circulation, which provokes activation and dysfunction of systemic vascular endothelium, producing less nitric oxide contributing to vasoconstriction, and promotes coagulation and greater sensitivity to vasopressors.

• #41 Eclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/253960-overview

  Many uterovascular changes occur when a woman is pregnant. It is believed that these changes are due to the interaction between fetal and maternal allografts and result in systemic and local vascular changes. It has been shown that in patients with eclampsia, the development of uteroplacental arteries is hindered. […] It is believed that in eclampsia there is abnormal cerebral blood flow in the setting of extreme hypertension. The regulation of cerebral perfusion is inhibited, vessels become dilated with increased permeability, and cerebral edema occurs, resulting in ischemia and encephalopathy. With increasing blood pressure, cerebral autoregulation is impaired resulting in cerebral regions of ischemia as well as microhemorrhage, each of which may initiate a seizure focus. […] Factors associated with endothelial dysfunction have been shown to be increased in the systemic circulation of women suffering from eclampsia. These include the following: Cellular fibronectin, Von Willebrand factor, Cell adhesion molecules (ie, P-selectin, vascular endothelial adhesion molecule-1 [VCAM-1]), Intercellular adhesion molecule-1 [ICAM-1]), Cytokines (ie, interleukin-6 [IL-6]), Tumor necrosis factor- [TNF-].

• #42 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  Preeclampsia is a serious complication of pregnancy where it affects 5–8% of all pregnancies. It increases the morbidity and mortality of both the fetus and pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidneys, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. […] At the renal level, glomerular endothelial injury leads to the development of maternal proteinuria. Actually, peripheral vasoconstriction secondary to maternal systemic inflammation and endothelial cell activation is sufficient for the development of preeclampsia-induced hypertension. Similarly, preeclampsia can cause hepatic and neurologic dysfunction due to vascular damage and/or hypertension. […] The current review summarizes recent development in the pathogenesis of preeclampsia with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for this disease state. Specifically, the review highlights the renal manifestations of the disease with emphasis on the involvement of angiogenic factors in vascular injury and on how restoration of the angiogenic balance affects renal and cardiovascular outcome of Preeclamptic women.

• #43 Modern concepts of etiology, pathogenesis and risk factors for preeclampsia – Abramova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/77046

  With PE, these processes are disrupted, which ultimately leads to defective trophoblast invasion and impaired formation of uteroplacental blood flow. […] One of the mechanisms that disrupt the invasion processes is the persistent hypoxia-mediated overexpression of HIF-1/HIF-2 and TGF-. […] Oxidative damage to the placenta induces apoptosis processes, such as the release of various antiangiogenic factors, proinflammatory cytokines, and vasoactive compounds into the mothers bloodstream, which develops major systemic endothelial cell dysfunction, accompanied by inflammation and vasoconstriction. […] Endothelial dysfunction is central to the maternal syndrome pathogenesis of PE and underlies the imbalance of vasoactive mediators, which induces a shift toward increased vasoconstrictor production.

• #44 Eclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/253960-overview

  In addition, it is believed that antiangiogenic factors, such as placental protein fms-like tyrosine kinase 1 (sFlt-1) and activin A, antagonize vascular endothelial growth factor (VEGF). Elevated levels of these proteins cause a reduction of VEGF and induce systemic and local endothelial cell dysfunction. […] Evidence indicates that leptin molecules increase in the circulation of women with eclampsia, inducing oxidative stress, another factor in eclampsia, on cells. […] The mechanism(s) responsible for the development of eclampsia remain(s) unclear. Genetic predisposition, immunology, endocrinology, nutrition, abnormal trophoblastic invasion, coagulation abnormalities, vascular endothelial damage, cardiovascular maladaptation, dietary deficiencies or excess, and infection have been proposed as etiologic factors for preeclampsia/eclampsia. […] Imbalanced prostanoid production and increased plasma antiphospholipids have also been implicated in eclampsia. In murine models, placental ischemia appears to be associated with an increased susceptibility to seizures and cerebrospinal fluid (CSF) inflammation.

• #45

  https://www.openaccessjournals.com/articles/pathophysiologyof-hypertension-inpreeclampsia.html

  However, the precise cause for both deficient spiral artery remodeling and its effects on the development of hypertension remain unclear. […] Placental ischemia is thought to cause hypoxia-induced release of placental factors, leading to widespread vascular and endothelial dysfunction. Endothelial dysfunction, which is associated with the development of hypertension, occurs due to an imbalance in angiogenic factors. […] Thus angiogenic factors have drawn increasing attention for their role in the pathogenesis of preeclampsia. […] Preeclampsia is characterized by an excess of anti-angiogenic factors with a simultaneous deficiency in pro-angiogenic factors. […] sFlt-1 appears to enact its anti-angiogenic effects through the antagonism of VEGF and PlGF. […] This effect of sFlt-1 is dose-dependent fashion, with a strong correlation of sFlt level and severity of disease.

• #46 Pathophysiology of Pre-Eclampsia—Two Theories of the Development of the Disease

  https://www.mdpi.com/1422-0067/25/1/307

  The most probable pathophysiological connection between the first stage of PE, characterized by impaired placental perfusion, and the subsequent second stage, marked by maternal endothelial dysfunction, is the increased production of anti-angiogenic factors by poorly perfused placentas in women who later develop PE. […] Maternal endothelial injury and dysfunction are responsible for the manifestation of most clinical symptoms characteristic of PE, including edema, thrombocytopenia, neurological complications, visual disturbances and proteinuria. […] The primary mechanism responsible for endothelial dysfunction in PE appears to be the anti-angiogenic activity of sFlt-1 and sEng, which are overproduced in women who develop PE. […] Although the two-stage model of PE is the most popular theory of the disease, the cardiac origin of PE must also be taken into consideration as a potential pathomechanism. A common element in both theories is impaired placental perfusion.

• #47 Eclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/253960-overview

  Many uterovascular changes occur when a woman is pregnant. It is believed that these changes are due to the interaction between fetal and maternal allografts and result in systemic and local vascular changes. It has been shown that in patients with eclampsia, the development of uteroplacental arteries is hindered. […] It is believed that in eclampsia there is abnormal cerebral blood flow in the setting of extreme hypertension. The regulation of cerebral perfusion is inhibited, vessels become dilated with increased permeability, and cerebral edema occurs, resulting in ischemia and encephalopathy. With increasing blood pressure, cerebral autoregulation is impaired resulting in cerebral regions of ischemia as well as microhemorrhage, each of which may initiate a seizure focus. […] Factors associated with endothelial dysfunction have been shown to be increased in the systemic circulation of women suffering from eclampsia. These include the following: Cellular fibronectin, Von Willebrand factor, Cell adhesion molecules (ie, P-selectin, vascular endothelial adhesion molecule-1 [VCAM-1]), Intercellular adhesion molecule-1 [ICAM-1]), Cytokines (ie, interleukin-6 [IL-6]), Tumor necrosis factor- [TNF-].

• #48 Preeclampsia and Eclampsia – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/antenatal-complications/preeclampsia-and-eclampsia

  Pathophysiology of preeclampsia and eclampsia is poorly understood. Factors may include poorly developed uterine placental spiral arterioles (which decrease uteroplacental blood flow during late pregnancy), a genetic abnormality, immunologic abnormalities, and placental ischemia or infarction. Lipid peroxidation of cell membranes induced by free radicals may contribute to preeclampsia. […] The coagulation system is activated, possibly secondary to endothelial cell dysfunction, leading to platelet activation.

• #49 Modern concepts of etiology, pathogenesis and risk factors for preeclampsia – Abramova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/77046

  With PE, these processes are disrupted, which ultimately leads to defective trophoblast invasion and impaired formation of uteroplacental blood flow. […] One of the mechanisms that disrupt the invasion processes is the persistent hypoxia-mediated overexpression of HIF-1/HIF-2 and TGF-. […] Oxidative damage to the placenta induces apoptosis processes, such as the release of various antiangiogenic factors, proinflammatory cytokines, and vasoactive compounds into the mothers bloodstream, which develops major systemic endothelial cell dysfunction, accompanied by inflammation and vasoconstriction. […] Endothelial dysfunction is central to the maternal syndrome pathogenesis of PE and underlies the imbalance of vasoactive mediators, which induces a shift toward increased vasoconstrictor production.

• #50 Preeclampsia: From Etiopathology to Organ Dysfunction | IntechOpen

  https://www.intechopen.com/chapters/79809

  Preeclampsia is a hypertensive disorder of pregnancy causing multi-organ dysfunction syndrome with placental dysfunction occurring in the latter half of pregnancy, with major cause of maternal morbidity, maternal intensive care admissions, Cesarean section, end-organ damage, and fetal complications. […] The pathogenesis includes endothelial activation and dysfunction leading to vasospasm. […] In preeclampsia, inflammatory mediators contributed by systemic oxidative stress are tumor necrosis factor alpha (TNF-Alpha) and interleukins that in turn lead to formation of lipid peroxidases, producing toxic radicals that injure systemic vascular endothelial cells. […] Injury to systemic endothelial cell is crucial in pathogenesis of preeclampsia and likely secretes placental protein factors into maternal circulation, which provokes activation and dysfunction of systemic vascular endothelium, producing less nitric oxide contributing to vasoconstriction, and promotes coagulation and greater sensitivity to vasopressors.

• #51 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  Preeclampsia is a serious complication of pregnancy where it affects 5–8% of all pregnancies. It increases the morbidity and mortality of both the fetus and pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidneys, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. […] At the renal level, glomerular endothelial injury leads to the development of maternal proteinuria. Actually, peripheral vasoconstriction secondary to maternal systemic inflammation and endothelial cell activation is sufficient for the development of preeclampsia-induced hypertension. Similarly, preeclampsia can cause hepatic and neurologic dysfunction due to vascular damage and/or hypertension. […] The current review summarizes recent development in the pathogenesis of preeclampsia with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for this disease state. Specifically, the review highlights the renal manifestations of the disease with emphasis on the involvement of angiogenic factors in vascular injury and on how restoration of the angiogenic balance affects renal and cardiovascular outcome of Preeclamptic women.

• #52 Pre-eclampsia – Wikipedia

  https://en.wikipedia.org/wiki/Pre-eclampsia

  Oxidative stress may also play an important part in the pathogenesis of pre-eclampsia. […] Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. […] It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. […] One hypothesis for vulnerability to pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus. […] In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. […] Immune factors may also play a role.

• #53 An Update Review of the Pathogenesis Hypothesis in Preeclampsia

  https://www.imrpress.com/journal/CEOG/49/8/10.31083/j.ceog4908170/htm

  At present, the pathogenesis of preeclampsia is still unclear, the theory of Genetic, Inflammatory Response, Immune Imbalance in Maternal-Fetal Interface, Oxidative Stress, Vascular Endothelial Cell Damage are supposed involved in the progress of preeclampsia. […] Although there are various theories mentioned above, none of them can fully explain all the biological behaviors of preeclampsia. More research is needed on the mechanism of preeclampsia.

• #54 Pre-eclampsia: its pathogenesis and pathophysiolgy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4928171/

  The exact mechanism for this is not known but various factors, such as abnormal genetic variations, biology of the trophoblasts or defective trophoblast differentiation acting together with extrinsic factors, such as maternal constitutional factors, action of macrophage defense mechanisms, impaired action of dNK cells and maternal endothelial cells have been advanced. […] It is therefore believed that placental ischaemiareperfusion injury is central to the development of PE. […] There is increasing evidence that suggests an imbalance between pro-angiogenic and anti-angiogenic factors are responsible for the pathophysiological effects seen in PE, and these appear before clinical signs are apparent. […] The disproportionate levels of anti-angiogenic factors such as sEng and sFlt-1, and pro-angiogenic factors such as VEGF, PlGF and TGF, are believed to cause generalised maternal endothelial dysfunctions, leading to hypertension, renal endotheliosis and blood coagulation.

• #55 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  The endothelial cell dysfunction that is characteristic of preeclampsia may be partially due to an extreme activation of leukocytes in the maternal circulation, as evidenced by an upregulation of type 1 helper T cells. […] Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with preeclampsia syndrome. In fact, studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. This is because the placental hypoperfusion resulting from the incomplete invasion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.

• #56 Pre-eclampsia: its pathogenesis and pathophysiolgy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4928171/

  The exact mechanism for this is not known but various factors, such as abnormal genetic variations, biology of the trophoblasts or defective trophoblast differentiation acting together with extrinsic factors, such as maternal constitutional factors, action of macrophage defense mechanisms, impaired action of dNK cells and maternal endothelial cells have been advanced. […] It is therefore believed that placental ischaemiareperfusion injury is central to the development of PE. […] There is increasing evidence that suggests an imbalance between pro-angiogenic and anti-angiogenic factors are responsible for the pathophysiological effects seen in PE, and these appear before clinical signs are apparent. […] The disproportionate levels of anti-angiogenic factors such as sEng and sFlt-1, and pro-angiogenic factors such as VEGF, PlGF and TGF, are believed to cause generalised maternal endothelial dysfunctions, leading to hypertension, renal endotheliosis and blood coagulation.

• #57 Eclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/253960-overview

  Many uterovascular changes occur when a woman is pregnant. It is believed that these changes are due to the interaction between fetal and maternal allografts and result in systemic and local vascular changes. It has been shown that in patients with eclampsia, the development of uteroplacental arteries is hindered. […] It is believed that in eclampsia there is abnormal cerebral blood flow in the setting of extreme hypertension. The regulation of cerebral perfusion is inhibited, vessels become dilated with increased permeability, and cerebral edema occurs, resulting in ischemia and encephalopathy. With increasing blood pressure, cerebral autoregulation is impaired resulting in cerebral regions of ischemia as well as microhemorrhage, each of which may initiate a seizure focus. […] Factors associated with endothelial dysfunction have been shown to be increased in the systemic circulation of women suffering from eclampsia. These include the following: Cellular fibronectin, Von Willebrand factor, Cell adhesion molecules (ie, P-selectin, vascular endothelial adhesion molecule-1 [VCAM-1]), Intercellular adhesion molecule-1 [ICAM-1]), Cytokines (ie, interleukin-6 [IL-6]), Tumor necrosis factor- [TNF-].

• #58 Preeclampsia: From Etiopathology to Organ Dysfunction | IntechOpen

  https://www.intechopen.com/chapters/79809

  Preeclampsia is a hypertensive disorder of pregnancy causing multi-organ dysfunction syndrome with placental dysfunction occurring in the latter half of pregnancy, with major cause of maternal morbidity, maternal intensive care admissions, Cesarean section, end-organ damage, and fetal complications. […] The pathogenesis includes endothelial activation and dysfunction leading to vasospasm. […] In preeclampsia, inflammatory mediators contributed by systemic oxidative stress are tumor necrosis factor alpha (TNF-Alpha) and interleukins that in turn lead to formation of lipid peroxidases, producing toxic radicals that injure systemic vascular endothelial cells. […] Injury to systemic endothelial cell is crucial in pathogenesis of preeclampsia and likely secretes placental protein factors into maternal circulation, which provokes activation and dysfunction of systemic vascular endothelium, producing less nitric oxide contributing to vasoconstriction, and promotes coagulation and greater sensitivity to vasopressors.

• #59 Pre-eclampsia – Wikipedia

  https://en.wikipedia.org/wiki/Pre-eclampsia

  Oxidative stress may also play an important part in the pathogenesis of pre-eclampsia. […] Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. […] It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. […] One hypothesis for vulnerability to pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus. […] In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. […] Immune factors may also play a role.

• #60 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Pre-eclampsia-Pathogenesis.aspx

  The exact pathology behind pre-eclampsia is unknown but is thought to involve abnormal development of the placenta due to problems with the blood vessels that supply it. […] Studies also suggest that abnormal immune responses to the fetus or to inflammatory triggers may cause pre-eclampsia. Women with pre-eclampsia have been shown to have increased levels of circulating fetal erythroblasts and cell-free fetal DNA. This points to a pathogenesis that involves placental lesions leaking fetal material into the mothers circulation and triggering immune reactions that cause endothelial damage and the symptoms of pre-eclampsia.

• #61 Modern concepts of etiology, pathogenesis and risk factors for preeclampsia – Abramova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/77046

  Evidence on the involvement of the renin-angiotensin-aldosterone system in PE pathogenesis has been obtained. […] Immune maladjustment of the mothers body also contributes to PE development. […] One of the components of the pathogenesis of PE is the deregulation of the complement system, which is most often associated with the presence of mutations in genes that control the biosynthesis of complement activation regulators. […] The main component of the arterial hypertension pathophysiology in PE is the biologically imbalanced active substances produced by endothelial cells, which are involved in vascular tone regulation. […] Therefore, as studied in the international and Russian literature, we can conclude that, firstly, despite numerous studies, no consensus was found on the molecular mechanisms of PE etiopathogenesis. […] Secondly, the key role in the development of this pregnancy complication is attributed to the processes of placentation disturbance, immune maladjustment of the mothers body, endothelial dysfunction, angiogenic imbalance, and others; however, their significance in the formation of early and late PE is considerably different.

• #62 Pre-eclampsia – Wikipedia

  https://en.wikipedia.org/wiki/Pre-eclampsia

  Oxidative stress may also play an important part in the pathogenesis of pre-eclampsia. […] Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. […] It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. […] One hypothesis for vulnerability to pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus. […] In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. […] Immune factors may also play a role.

• #63 Molecular pathogenesis of preeclampsia | Cornell University College of Veterinary Medicine

  https://www.vet.cornell.edu/research/labs/davisson-lab/current-projects/projects/molecular-pathogenesis-preeclampsia

  As part of our overall goal of understanding the complex mechanisms underlying hypertensive disorders, we have recently begun to focus on a new line of investigation – the molecular pathogenesis of preeclampsia. […] Defined by the clinical constellation of hypertension and renal disease in the last trimester of pregnancy, preeclampsia impacts up to 10% of pregnancies and is a leading cause of maternal and fetal morbidity and mortality. Despite its common occurrence and serious consequences, progress in understanding the pathophysiology of this disorder has been slow. Clinical studies have been limited by the difficulty of testing hypotheses in an urgent, high-risk setting. Basic research has been hampered by the lack of an animal model that fully recapitulates the clinical disorder. […] We recently identified and characterized a genetic murine model (BPH/5) that spontaneously develops the relevant clinical sequelae of the disorder including development of frank hypertension and renal disease in the last trimester of pregnancy that resolves upon delivery.

• #64 Molecular pathogenesis of preeclampsia | Cornell University College of Veterinary Medicine

  https://www.vet.cornell.edu/research/labs/davisson-lab/current-projects/projects/molecular-pathogenesis-preeclampsia

  This model provides an exciting new opportunity for elucidating the molecular mechanisms of this devastating human disease, and a host of studies are ongoing including: analysis of several candidate molecules including VEGF and reactive oxygen species, reciprocal embryo transfer experiments in the context of lentiviral-mediated gene manipulation of blastocysts, mRNA, miRNA and protein profiling of BPH/5 placentas, genetic mapping of the preeclampsia locus.

• #65 African women at higher risk of pre-eclampsia—a dangerous pregnancy complication

  https://medicalxpress.com/news/2025-05-african-women-higher-pre-eclampsia.html

  Pre-eclampsia is a danger to pregnant women. It’s a complication characterized by high blood pressure and organ damage, arising during the second half of pregnancy, in labor or in the first week after delivery. […] Yet we still do not know enough about pre-eclampsia. This gap has driven my research into the disease. […] The precise causes of pre-eclampsia are not certain, but factors beyond genetics are thought to be problems with the immune system and inadequate development of the placenta. But much of what researchers know comes from work done in high-income countries, often with a limited sample size of African women. […] Building on my findings about genetic determinants, I am leading a research team at Makerere University to design interventions tailored to specific prevention and treatment strategies for African populations.

• #66 Pre-eclampsia – Wikipedia

  https://en.wikipedia.org/wiki/Pre-eclampsia

  Oxidative stress may also play an important part in the pathogenesis of pre-eclampsia. […] Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. […] It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. […] One hypothesis for vulnerability to pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus. […] In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. […] Immune factors may also play a role.

• #67 Research trajectory of the mechanism of preeclampsia: a scientometric perspective | Journal of Health, Population and Nutrition | Full Text

  https://jhpn.biomedcentral.com/articles/10.1186/s41043-025-00806-5

  The imbalance between pro-angiogenic factors and anti-angiogenic factors in the maternal circulation leads to endothelial dysfunction and triggers the occurrence of preeclampsia. […] The occurrence of preeclampsia is often linked to abnormal epigenetic regulation. […] Changes in maternal intestinal flora have been closely linked to the onset and progression of preeclampsia.

• #68 African women at higher risk of pre-eclampsia—a dangerous pregnancy complication

  https://medicalxpress.com/news/2025-05-african-women-higher-pre-eclampsia.html

  More resources must be allocated to genetics research to realize our goals of prevention, early detection, diagnosis and treatment of pre-eclampsia and its associated complications. […] Moreover, investigating the genetic roots of pre-eclampsia could lead to novel therapies that reduce the need for costly medical procedures or prolonged care for those affected.

• #69 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  It is now appreciated that early- and late-onset pre-eclampsia have different pathophysiologies, thus advancing our understanding of the syndrome. In early-onset, also referred to as placental pre-eclampsia, there is clear evidence of reduced maternal spiral artery conversion in early pregnancy. This is associated with placental malperfusion, and gross and molecular pathology of the placental tissues. Oxidative stress of the placenta causes increased secretion of sFLT-1 and reduced PlGF, reflecting the biomarker patterns. In late-onset pre-eclampsia, called also maternal preeclampsia, there is little evidence of reduced arterial conversion and placental perfusion is maintained or even increased. […] These cases, which represent nearly 80% of pre-eclampsia, are now thought to be due to a genetic maternal pre-disposition to cardiovascular disease, which manifests as pre-eclampsia during the stress-test of pregnancy.

• #70 Modern concepts of etiology, pathogenesis and risk factors for preeclampsia – Abramova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/77046/en_US

  Generally, the mechanisms of early and late PE occurrence are different. […] Thus, late PE development, which was registered in 88% of all cases, is mainly due to maternal causes (metabolic syndrome, arterial hypertension, chronic kidney disease, etc.) in combination with placental dysfunction. […] Early-onset was noted in 12% of PE cases and is associated with extensive placental lesions and a higher risk of maternal and fetal complications. A trigger factor for early PE is a placentation impairment at the initial gestational stages. […] With PE, these processes are disrupted, which ultimately leads to defective trophoblast invasion and impaired formation of uteroplacental blood flow. […] One of the mechanisms that disrupt the invasion processes is the persistent hypoxia-mediated overexpression of HIF-1/HIF-2 and TGF-.

• #71 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  It is now appreciated that early- and late-onset pre-eclampsia have different pathophysiologies, thus advancing our understanding of the syndrome. In early-onset, also referred to as placental pre-eclampsia, there is clear evidence of reduced maternal spiral artery conversion in early pregnancy. This is associated with placental malperfusion, and gross and molecular pathology of the placental tissues. Oxidative stress of the placenta causes increased secretion of sFLT-1 and reduced PlGF, reflecting the biomarker patterns. In late-onset pre-eclampsia, called also maternal preeclampsia, there is little evidence of reduced arterial conversion and placental perfusion is maintained or even increased. […] These cases, which represent nearly 80% of pre-eclampsia, are now thought to be due to a genetic maternal pre-disposition to cardiovascular disease, which manifests as pre-eclampsia during the stress-test of pregnancy.

• #72 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  It is now appreciated that early- and late-onset pre-eclampsia have different pathophysiologies, thus advancing our understanding of the syndrome. In early-onset, also referred to as placental pre-eclampsia, there is clear evidence of reduced maternal spiral artery conversion in early pregnancy. This is associated with placental malperfusion, and gross and molecular pathology of the placental tissues. Oxidative stress of the placenta causes increased secretion of sFLT-1 and reduced PlGF, reflecting the biomarker patterns. In late-onset pre-eclampsia, called also maternal preeclampsia, there is little evidence of reduced arterial conversion and placental perfusion is maintained or even increased. […] These cases, which represent nearly 80% of pre-eclampsia, are now thought to be due to a genetic maternal pre-disposition to cardiovascular disease, which manifests as pre-eclampsia during the stress-test of pregnancy.

• #73 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  It is now appreciated that early- and late-onset pre-eclampsia have different pathophysiologies, thus advancing our understanding of the syndrome. In early-onset, also referred to as placental pre-eclampsia, there is clear evidence of reduced maternal spiral artery conversion in early pregnancy. This is associated with placental malperfusion, and gross and molecular pathology of the placental tissues. Oxidative stress of the placenta causes increased secretion of sFLT-1 and reduced PlGF, reflecting the biomarker patterns. In late-onset pre-eclampsia, called also maternal preeclampsia, there is little evidence of reduced arterial conversion and placental perfusion is maintained or even increased. […] These cases, which represent nearly 80% of pre-eclampsia, are now thought to be due to a genetic maternal pre-disposition to cardiovascular disease, which manifests as pre-eclampsia during the stress-test of pregnancy.

• #74 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  It is now appreciated that early- and late-onset pre-eclampsia have different pathophysiologies, thus advancing our understanding of the syndrome. In early-onset, also referred to as placental pre-eclampsia, there is clear evidence of reduced maternal spiral artery conversion in early pregnancy. This is associated with placental malperfusion, and gross and molecular pathology of the placental tissues. Oxidative stress of the placenta causes increased secretion of sFLT-1 and reduced PlGF, reflecting the biomarker patterns. In late-onset pre-eclampsia, called also maternal preeclampsia, there is little evidence of reduced arterial conversion and placental perfusion is maintained or even increased. […] These cases, which represent nearly 80% of pre-eclampsia, are now thought to be due to a genetic maternal pre-disposition to cardiovascular disease, which manifests as pre-eclampsia during the stress-test of pregnancy.

• #75 Preeclampsia – Pregnancy-Related Hypertension – Pregnancy-Related Conditions – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.2.20.4.1.

  In the early-onset preeclampsia phenotype, maladaptive maternal cardiovascular changes can be seen before the development of overt disease. Cardiac output is low with high peripheral vascular resistance. This is the opposite of the second phenotype, which typically has a later onset, with an increased cardiac output and low peripheral vascular resistance. […] Tailoring antihypertensive therapy to the underlying maternal hemodynamic profile is an emerging frontier in preeclampsia research.

• #76 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  Preeclampsia is characterized by endothelial dysfunction in pregnant women. Therefore, the possibility exists that preeclampsia may be a contributor to future cardiovascular disease. In a meta-analysis, several associations were observed between an increased risk of cardiovascular disease and a pregnancy complicated by preeclampsia. These associations included an approximately 4-fold increase in the risk of subsequent development of hypertension and an approximately 2-fold increase in the risk of ischemic heart disease, venous thromboembolism, and stroke. Moreover, women who had recurrent preeclampsia were more likely to have hypertension later in life. […] The mechanisms by which preeclampsia occurs is not certain, and numerous maternal, paternal, and fetal factors have been implicated in its development. The factors considered to be the most important include the following: Maternal immunologic intolerance, Abnormal placental implantation, Genetic, nutritional, and environmental factors, Cardiovascular and inflammatory changes.

• #77 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  Preeclampsia is characterized by endothelial dysfunction in pregnant women. Therefore, the possibility exists that preeclampsia may be a contributor to future cardiovascular disease. In a meta-analysis, several associations were observed between an increased risk of cardiovascular disease and a pregnancy complicated by preeclampsia. These associations included an approximately 4-fold increase in the risk of subsequent development of hypertension and an approximately 2-fold increase in the risk of ischemic heart disease, venous thromboembolism, and stroke. Moreover, women who had recurrent preeclampsia were more likely to have hypertension later in life. […] The mechanisms by which preeclampsia occurs is not certain, and numerous maternal, paternal, and fetal factors have been implicated in its development. The factors considered to be the most important include the following: Maternal immunologic intolerance, Abnormal placental implantation, Genetic, nutritional, and environmental factors, Cardiovascular and inflammatory changes.

• #78 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  Preeclampsia is characterized by endothelial dysfunction in pregnant women. Therefore, the possibility exists that preeclampsia may be a contributor to future cardiovascular disease. In a meta-analysis, several associations were observed between an increased risk of cardiovascular disease and a pregnancy complicated by preeclampsia. These associations included an approximately 4-fold increase in the risk of subsequent development of hypertension and an approximately 2-fold increase in the risk of ischemic heart disease, venous thromboembolism, and stroke. Moreover, women who had recurrent preeclampsia were more likely to have hypertension later in life. […] The mechanisms by which preeclampsia occurs is not certain, and numerous maternal, paternal, and fetal factors have been implicated in its development. The factors considered to be the most important include the following: Maternal immunologic intolerance, Abnormal placental implantation, Genetic, nutritional, and environmental factors, Cardiovascular and inflammatory changes.

• #79 Preeclampsia: Pathophysiology and Clinical Presentations

  https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2020/09/30/19/20/Preeclampsia-Pathophysiology-and

  Preeclampsia is a hypertensive disorder of pregnancy that occurs in 2-8% of pregnancies and causes substantial morbidity and mortality. […] The complex pathophysiology of preeclampsia begins with abnormal placental development, endothelial dysfunction, and immunologic aberrations, possibly related to genetic susceptibility. […] Hypertension is necessary for the diagnosis of preeclampsia, defined as systolic blood pressure (SBP) 140 mm Hg or diastolic BP (DBP) 90 mm Hg on two occasions 4 hours apart after 20 weeks gestation in a woman with previously normal BP; or SBP 160 mm Hg or DBP 110 mm Hg on one occasion. […] The imbalance between proangiogenic and antiangiogenic factors likely causes podocyte injury leading to increased risk of hypertension and chronic kidney disease. […] Inflammatory cytokines lead to endothelial dysfunction and thrombotic microangiopathy of the kidneys, and decreased intravascular volumes in preeclampsia increases sodium and free-water retention.

• #80 Preeclampsia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1476919-overview

  Preeclampsia is characterized by endothelial dysfunction in pregnant women. Therefore, the possibility exists that preeclampsia may be a contributor to future cardiovascular disease. In a meta-analysis, several associations were observed between an increased risk of cardiovascular disease and a pregnancy complicated by preeclampsia. These associations included an approximately 4-fold increase in the risk of subsequent development of hypertension and an approximately 2-fold increase in the risk of ischemic heart disease, venous thromboembolism, and stroke. Moreover, women who had recurrent preeclampsia were more likely to have hypertension later in life. […] The mechanisms by which preeclampsia occurs is not certain, and numerous maternal, paternal, and fetal factors have been implicated in its development. The factors considered to be the most important include the following: Maternal immunologic intolerance, Abnormal placental implantation, Genetic, nutritional, and environmental factors, Cardiovascular and inflammatory changes.

• #81 Frontiers | Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00973/full

  In the last decade, our understanding of the pathogenesis of preeclampsia has progressively advanced. Therefore, in this section we will focus on the most recent concepts in the pathogenesis of the disease, especially the involvement of angiogenic factors. It is obvious today that preeclampsia is a systemic disease characterized by generalized endothelial damage, thus negatively affecting almost all organs of preeclamptic women, including the potential to affect future cardiovascular and renal diseases even decades after the disease occurrence. […] The situation was even grimmer in women who experienced preeclampsia by 34 weeks of gestation. The high mortality rate could be explained by the findings that early-onset preeclampsia conferred a substantially higher risk of cardiovascular, respiratory, CNS, renal, hepatic, and other morbidity and was evident by end target damage. Collectively, these findings suggest that the risk of morbidity/mortality among preeclamptic women is related to the severity the disease and gestational age at onset, namely early (<34 weeks) or late (>34 weeks).

• #82 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #83 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  Molecular mechanisms that mediate spiral artery remodelling are still being debated. […] Thus, the concept of defective placentation and failure to transform uterine spiral arteries has emerged as central to the pathogenesis of pre-eclampsia. […] Oxidative stress also occurs at the maternalfetal interface and is thought to have a key role in normal and defective placental development. […] The concept of a maternal predisposition to pre-eclampsia has been posited and supported by extensive work done at the vascular level of affected mothers. […] The hallmarks of pre-eclampsia are not confined to the placenta but also extend to widespread effects in the mother that can be collectively viewed as the maternal syndrome. […] Experimental and epidemiological studies support a pathological role for imbalance in circulating angiogenic factors in the aetiology of the maternal syndrome. Excess levels of the antiangiogenic factor sFLT1, which is produced in the placenta and released into the maternal circulation, induce maternal endothelial dysfunction leading to preeclamptic signs and symptoms. […] High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials.

• #84 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #85 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #86 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #87 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #88 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #89 Mechanisms of Disease: pre-eclampsia | Nature Reviews Nephrology

  https://www.nature.com/articles/ncpneph0035

  Pre-eclampsia results from placental hypoperfusion secondary to impaired establishment of uteroplacental vasculature […] Abnormal biology of extravillous trophoblasts, decidua, uterine natural killer cells and maternal endothelium have pathogenic roles […] Hypothesis: placental overexpression of arginase decreases L-arginine, reducing activity of the vasodilator nitric oxide […] Hypothesis: hypoxia secondary to placental hypoperfusion induces release of soluble Fms-like tyrosine kinase 1 and reactive oxygen species into the maternal circulation, initiating endothelial dysfunction […] The hypertension and proteinuria characteristic of pre-eclampsia might be ameliorated by supplementation with L-arginine or antioxidants, or by blocking Fms-like tyrosine kinase 1.

• #90 Extracellular Vesicles and Preeclampsia: From Pathogenesis to Diagnostics and Therapeutics

  https://www.izon.com/news/extracellular-vesicles-and-preeclampsia

  Placental EVs in preeclampsia reduce the availability of nitric oxide (a key vasodilator and antioxidant) for endothelial cells by carrying less nitric oxide synthase compared to EVs from healthy placentas, and by carrying increased miR-155 which reduces expression of endothelial nitric oxide synthase. […] Given that there are more syncytiotrophoblast EVs released in preeclampsia, the impact of placental-derived EVs in preeclampsia could be a significant contributor to pathogenesis. […] If EVs contribute to preeclampsia pathogenesis, could other EVs be harnessed for treatment? […] These studies provide hope that EV based treatments for preeclampsia could prove fruitful.

• #91 Low-Dose Aspirin Use During Pregnancy | ACOG

  https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2018/07/low-dose-aspirin-use-during-pregnancy

  Aspirin (acetylsalicylic acid) is a nonsteroidal antiinflammatory drug (NSAID) that works primarily through its inhibition of two cyclooxygenase isoenzymes (COX-1 and COX-2), which are necessary for prostaglandin biosynthesis. The COX-1 isoform is present in the vascular endothelium and regulates the production of prostacyclin and thromboxane A 2, prostaglandins with opposing regulatory effects on vascular homeostasis and platelet function. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation, whereas thromboxane A 2 (TXA2) is a potent vasoconstrictor and promotes platelet aggregation. The COX-2 isoform is inducible and expressed almost exclusively following exposure to cytokines or other inflammatory mediators. The effect of aspirin on COX-dependent prostaglandin synthesis is dose dependent. At lower dosages (60150 mg/day) aspirin irreversibly acetylates COX-1, resulting in decreased platelet synthesis of TXA2 without affecting vascular wall production of prostacyclin. At higher doses, aspirin inhibits both COX-1 and COX-2, effectively blocking all prostaglandin production.

• #92 Low-Dose Aspirin Use During Pregnancy | ACOG

  https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2018/07/low-dose-aspirin-use-during-pregnancy

  Aspirin (acetylsalicylic acid) is a nonsteroidal antiinflammatory drug (NSAID) that works primarily through its inhibition of two cyclooxygenase isoenzymes (COX-1 and COX-2), which are necessary for prostaglandin biosynthesis. The COX-1 isoform is present in the vascular endothelium and regulates the production of prostacyclin and thromboxane A 2, prostaglandins with opposing regulatory effects on vascular homeostasis and platelet function. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation, whereas thromboxane A 2 (TXA2) is a potent vasoconstrictor and promotes platelet aggregation. The COX-2 isoform is inducible and expressed almost exclusively following exposure to cytokines or other inflammatory mediators. The effect of aspirin on COX-dependent prostaglandin synthesis is dose dependent. At lower dosages (60150 mg/day) aspirin irreversibly acetylates COX-1, resulting in decreased platelet synthesis of TXA2 without affecting vascular wall production of prostacyclin. At higher doses, aspirin inhibits both COX-1 and COX-2, effectively blocking all prostaglandin production.

• #93 Low-Dose Aspirin Use During Pregnancy | ACOG

  https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2018/07/low-dose-aspirin-use-during-pregnancy

  Evidence suggesting that an imbalance in prostacyclin and TXA2 metabolism was involved in the development of preeclampsia prompted the initial studies of aspirin for preeclampsia prevention because of its preferential inhibition of TXA2 at lower doses. However, it is likely that preeclampsia is a result of poor placentation from a variety of causes, including ischemia, reperfusion, or dysfunctional maternal inflammatory response towards the trophoblast. Whether low-dose aspirin improves early placental perfusion is unknown, and likewise, the precise mechanism by which low-dose aspirin prevents preeclampsia in some women is also uncertain.

• #94 Preeclampsia: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/preeclampsia-pathogenesis/print

  Preeclampsia is a pregnancy-specific syndrome characterized by the onset of hypertension and proteinuria or hypertension and end-organ dysfunction with or without proteinuria after 20 weeks of gestation. […] The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. Abnormalities in the development of placental vasculature early in pregnancy may result in relative placental underperfusion/hypoxia/ischemia, which leads to the progressive release of antiangiogenic factors into the maternal circulation that alter maternal systemic endothelial function and cause hypertension, vasospasm, platelet aggregation, and the other manifestations of the disease. […] However, the trigger for abnormal placental development and the subsequent cascade of events remains unknown.

• #95 Pathophysiology of Pre-Eclampsia—Two Theories of the Development of the Disease

  https://www.mdpi.com/1422-0067/25/1/307

  Pre-eclampsia (PE) continues to be a leading cause of maternal and fetal mortality and morbidity. While substantial progress has been made in understanding the pathomechanisms of PE, the pathophysiology of the disease is still not fully understood. While the “two-stage model” of the development of PE is the most widely accepted theory, stating that the placenta is the main source of the disease, there are some other pathophysiological models of PE. […] The prevailing and most plausible theory regarding the development of PE is the two-stage theory. In this model, the first stage of the disease involves impaired placentation and reduced placental perfusion, while the second stage encompasses general maternal endothelial damage and dysfunction. […] According to this theory, the initial reduction in placental perfusion is mainly caused by disruptions in the process of placental development, known as placentation. This disturbance arises from impaired trophoblast invasion into the spiral arteries during the first half of pregnancy.

• #96 Preeclampsia: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/preeclampsia-pathogenesis/print

  Preeclampsia is a pregnancy-specific syndrome characterized by the onset of hypertension and proteinuria or hypertension and end-organ dysfunction with or without proteinuria after 20 weeks of gestation. […] The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. Abnormalities in the development of placental vasculature early in pregnancy may result in relative placental underperfusion/hypoxia/ischemia, which leads to the progressive release of antiangiogenic factors into the maternal circulation that alter maternal systemic endothelial function and cause hypertension, vasospasm, platelet aggregation, and the other manifestations of the disease. […] However, the trigger for abnormal placental development and the subsequent cascade of events remains unknown.

• #97 Pre-eclampsia: pathogenesis, novel diagnostics and therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6472952/

  Molecular mechanisms that mediate spiral artery remodelling are still being debated. […] Thus, the concept of defective placentation and failure to transform uterine spiral arteries has emerged as central to the pathogenesis of pre-eclampsia. […] Oxidative stress also occurs at the maternalfetal interface and is thought to have a key role in normal and defective placental development. […] The concept of a maternal predisposition to pre-eclampsia has been posited and supported by extensive work done at the vascular level of affected mothers. […] The hallmarks of pre-eclampsia are not confined to the placenta but also extend to widespread effects in the mother that can be collectively viewed as the maternal syndrome. […] Experimental and epidemiological studies support a pathological role for imbalance in circulating angiogenic factors in the aetiology of the maternal syndrome. Excess levels of the antiangiogenic factor sFLT1, which is produced in the placenta and released into the maternal circulation, induce maternal endothelial dysfunction leading to preeclamptic signs and symptoms. […] High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials.

• #98 Pre-eclampsia: pathogenesis, novel diagnostics and therapies | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-019-0119-6

  High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials. […] Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction. […] Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. […] This key paper demonstrates that excess sFLT1 is sufficient to induce pre-eclampsia. […] This large prospective clinical study demonstrates a utility for serum angiogenic biomarkers in women with suspected pre-eclampsia.

• #99 African women at higher risk of pre-eclampsia—a dangerous pregnancy complication

  https://medicalxpress.com/news/2025-05-african-women-higher-pre-eclampsia.html

  More resources must be allocated to genetics research to realize our goals of prevention, early detection, diagnosis and treatment of pre-eclampsia and its associated complications. […] Moreover, investigating the genetic roots of pre-eclampsia could lead to novel therapies that reduce the need for costly medical procedures or prolonged care for those affected.

• #100 Preeclampsia – Pregnancy-Related Hypertension – Pregnancy-Related Conditions – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.2.20.4.1.

  In the early-onset preeclampsia phenotype, maladaptive maternal cardiovascular changes can be seen before the development of overt disease. Cardiac output is low with high peripheral vascular resistance. This is the opposite of the second phenotype, which typically has a later onset, with an increased cardiac output and low peripheral vascular resistance. […] Tailoring antihypertensive therapy to the underlying maternal hemodynamic profile is an emerging frontier in preeclampsia research.

• #101 An Update Review of the Pathogenesis Hypothesis in Preeclampsia

  https://www.imrpress.com/journal/CEOG/49/8/10.31083/j.ceog4908170/htm

  At present, the pathogenesis of preeclampsia is still unclear, the theory of Genetic, Inflammatory Response, Immune Imbalance in Maternal-Fetal Interface, Oxidative Stress, Vascular Endothelial Cell Damage are supposed involved in the progress of preeclampsia. […] Although there are various theories mentioned above, none of them can fully explain all the biological behaviors of preeclampsia. More research is needed on the mechanism of preeclampsia.

• #102 Modern concepts of etiology, pathogenesis and risk factors for preeclampsia – Abramova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/77046/en_US

  Immune maladjustment of the mothers body also contributes to PE development. […] One of the components of the pathogenesis of PE is the deregulation of the complement system, which is most often associated with the presence of mutations in genes that control the biosynthesis of complement activation regulators. […] The main component of the arterial hypertension pathophysiology in PE is the biologically imbalanced active substances produced by endothelial cells, which are involved in vascular tone regulation. […] To date, a large number of studies have been conducted that comprise the information about 130 possible PE risk factors, covering a large list of comorbidities, biomarkers, environmental factors, and genetic determinants. […] Thus, the existing contradictions and insufficient consensus of certain biological processes involved in PE development necessitate a further study of this pregnancy complication.

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