Materiały źródłowe

• #1 Cerebral Aneurysm – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507902/

  Cerebral aneurysms are defined as dilations that occur at weak points along the arterial circulation within the brain. […] Most cerebral aneurysms are acquired lesions, with an increased incidence in patients with certain risk factors such as advanced age, hypertension, smoking, alcohol abuse, and atherosclerosis. […] It is believed that a multifactorial process leads to the formation of saccular aneurysms. Hemodynamic stress on the internal elastic lamina causes breakdown over time. This is coupled with vibrations from turbulent blood flow, causing structural fatigue. There is also evidence that T-cell and macrophage-mediated inflammation causes histologic changes within the vascular wall contributing to aneurysmal formation and growth. The process is expedited and amplified in patients with certain risk factors as described previously. Conversely, fusiform aneurysms are predominantly caused by atherosclerosis and mycotic aneurysms from septic emboli present in infectious endocarditis.

• #1 The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture in: Neurosurgical Focus Volume 47 Issue 1 (2019) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/47/1/article-pE11.xml

  The pathogenesis of intracranial aneurysms remains complex and multifactorial. While vascular, genetic, and epidemiological factors play a role, nascent aneurysm formation is believed to be induced by hemodynamic forces. Hemodynamic stresses and vascular insults lead to additional aneurysm and vessel remodeling. […] Advanced imaging techniques allow us to better define the roles of aneurysm and vessel morphology and hemodynamic parameters, such as wall shear stress, oscillatory shear index, and patterns of flow on aneurysm formation, growth, and rupture. While a complete understanding of the interplay between these hemodynamic variables remains elusive, the authors review the efforts that have been made over the past several decades in an attempt to elucidate the physical and biological interactions that govern aneurysm pathophysiology. Furthermore, the current clinical utility of hemodynamics in predicting aneurysm rupture is discussed.

• #1 New Pathophysiological Considerations on Cerebral Aneurysms

  https://neurointervention.org/journal/view.php?doi=10.5469/neuroint.2018.01011

  The extracellular matrix is a dynamic structure that is continuously undergoing a remodeling process by interacting with vascular cells. […] High wall shear stress induces endothelial cell damage, smooth muscle cell degeneration, and media thinning. Hemodynamic forces also cause endothelial cells and smooth muscle cells to release MMP-2 and MMP-9 and subsequently to degrade the extracellular matrix, resulting in aneurysm formation. […] Cerebral aneurysms have been histologically characterized by acute and chronic inflammation and medial wall degeneration. Numerous immunologic factors have been identified as initiators and inducers of cerebral aneurysm development. High hemodynamic stress alters endothelial function and induces an infiltration of inflammatory cells and activation of downstream cascades in the tunica media.

• #1 Intracranial aneurysm – Wikipedia

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

  Both high and low wall shear stress of flowing blood can cause aneurysm and rupture. However, the mechanism of action is still unknown. It is speculated that low shear stress causes growth and rupture of large aneurysms through inflammatory response while high shear stress causes growth and rupture of small aneurysm through mural response (response from the blood vessel wall). […] Damage to structural integrity of the arterial wall by shear stress causes an inflammatory response with the recruitment of T cells, macrophages, and mast cells. […] The inflammatory mediators are: interleukin 1 beta, interleukin 6, tumor necrosis factor alpha (TNF alpha), MMP1, MMP2, MMP9, prostaglandin E2, complement system, reactive oxygen species (ROS), and angiotensin II. […] This causes the fibrosis of the arterial wall, with reduction of number of smooth muscle cells, abnormal collagen synthesis, resulting in a thinning of the arterial wall and the formation of aneurysm and rupture.

• #1 Cerebral Aneurysm: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1161518-overview

  The pathogenesis of cerebral aneurysms is related inherently to structural aberrations of the cerebrovasculature, although the etiology of these abnormalities may be diverse. The integrity of the internal elastic lamina is compromised, with associated elastic defects in the adjacent layers of the tunica media and adventitia. Muscular defects of the tunica media and minimal support of adjacent brain parenchyma augment the pathologic potential of chronic hemodynamic stress on the arterial wall. Focal turbulence and discontinuity of the normal architecture at vessel bifurcations may account for the propensity of saccular aneurysm formation at these locations. Distal aneurysms may be smaller compared with proximal sites, yet the risk of rupture may be dissimilar due to the relatively thinner parent artery wall thickness.

• #1 The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture in: Neurosurgical Focus Volume 47 Issue 1 (2019) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/47/1/article-pE11.xml

  Despite not knowing the exact mechanism involved, a recent report by Cebral et al. supports the theory that different hemodynamic conditions are associated with different aneurysm phenotypes. […] Abnormal hemodynamics serves as a trigger for vascular modeling and the biochemical mechanisms that persist following the inciting stressor. […] In the presence of hemodynamic stressors, flow-dependent NO release inhibits the proliferation of VSMCs and can initiate apoptosis by activating caspase 3. […] The disappearance of the IEL is among the first histological changes observed during aneurysmal growth, leaving the adventitia as the only layer resisting transmural blood pressure. […] As imaging studies and computational modeling continue to improve, understanding of the hemodynamic role in cerebral aneurysm formation, growth, and rupture will increase.

• #1 New Pathophysiological Considerations on Cerebral Aneurysms

  https://neurointervention.org/journal/view.php?number=236

  This review deals with the basic knowledge and advanced concepts underlying the pathophysiology of cerebral aneurysms. […] Although the exact pathogenesis of cerebral aneurysm formation, growth, and rupture remains to be established, extracellular matrix defects and degeneration, hemodynamic stress, and inflammatory responses have been suggested as key components leading to structural fragility in the arterial wall. […] The perturbations of structural component are specified in Table 1. […] The longevity of elastin generated in early embryogenesis is similar to the human life span, and rarely experiences a wear and tear process. […] Once extracellular matrix defects or degradation take place, the disease course may not be restored. […] An imbalance between MMPs and their inhibitors contributes to initiation and progression of cerebral aneurysms.

• #1 Intracranial Aneurysm Development 101: Pathogenesis and Risk Factors

  https://consultqd.clevelandclinic.org/intracranial-aneurysm-development-101-pathogenesis-and-risk-factors

  Evidence mounts that inflammation plays a key role […] Recently, increased focus has been placed on the role of inflammation in causing vascular smooth muscle dysfunction, driving both aneurysm formation and rupture, especially in vulnerable individuals. […] The role of inflammation in aneurysm pathogenesis is an important focus of research. Current evidence points to a complex interplay between endothelial dysfunction, inflammatory responses and flow dynamics that eventually leads to aneurysm rupture. […] Areas of vessel dysfunction or injury attract macrophages, mast cells and T cells, which then contribute to alteration of vascular smooth muscle cells. As macrophages release cytokines and other mediators, matrix metalloproteinases cleave the extracellular matrix, inducing a positive feedback cycle that further promotes migration of inflammatory cells.

• #1 Pathogenesis, Diagnosis and Treatment of the Cerebral Aneurysm

  https://www.iomcworld.org/open-access/pathogenesis-diagnosis-and-treatment-of-the-cerebral-aneurysm-83456.html

  Damage to structural integrity of the arterial wall by shear stress causes an inflammatory response with the recruitment of T cells, macrophages, and mast cells. […] The inflammatory mediators are: interleukin 1 beta, interleukin 6, tumor necrosis factor alpha (TNF alpha), MMP1, MMP2, MMP9, prostaglandin E2, complement system, reactive oxygen species (ROS), and angiotensin II. […] This causes the fibrosis of the arterial wall, with reduction of number of smooth muscle cells, abnormal collagen synthesis, resulting in a thinning of the arterial wall and the formation of aneurysm and rupture. […] No specific gene loci has been identified to be associated with cerebral aneurysms.

• #1 The Role of NF-κB in Intracranial Aneurysm Pathogenesis: A Systematic Review

  https://www.mdpi.com/1422-0067/24/18/14218

  Intracranial aneurysms (IAs) are abnormal dilations of the cerebral vessels, which pose a persistent threat of cerebral hemorrhage. Inflammation is known to contribute to IA development. The nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB) is the major driver of inflammation. It increases the expression of inflammatory markers and matrix metalloproteinases (MMPs), which contribute heavily to the pathogenesis of IAs. NF-κB activation has been linked to IA rupture and resulting subarachnoid hemorrhage. Moreover, NF-κB activation can result in endothelial dysfunction, smooth muscle cell phenotypic switching, and infiltration of inflammatory cells in the arterial wall, which subsequently leads to the initiation and progression of IAs and consequently results in rupture.

• #1

  https://link.springer.com/article/10.1007/s12975-013-0290-1

  Vascular smooth muscle cells (SMC) maintain significant plasticity. Following environmental stimulation, SMC can alter their phenotype from one primarily concerned with contraction to a pro-inflammatory and matrix remodeling phenotype. […] Evolving evidence demonstrates that SMCs and phenotypic modulation play a significant role in cerebral aneurysm formation and rupture. […] Pharmacological alteration of smooth muscle cell function and phenotypic modulation could provide a promising medical therapy to inhibit cerebral aneurysm progression. […] This study reviews vascular SMC function and its contribution to cerebral aneurysm pathophysiology.

• #1 Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

  https://www.oaepublish.com/articles/2347-8659.154433

  Intracranial aneurysms are a life-threatening cerebrovascular pathology with a probability of spontaneous rupture. Recent investigation has reinforced inflammation’s role in the pathophysiological process of cerebral aneurysms. The majority of evidence from intensive investigation has implicated a mounting inflammatory response during the aneurysm pathogenesis. Hemodynamic insult is considered to be one of the first steps in activating the cerebral vessel walls’ inflammatory response. Upon the hemodynamic insult, this balance is perturbed, leading to vessel wall weakening. Dilation results, as extracellular matrix is degraded by increased levels of matrix metalloproteinases (MMP) compounded by concomitant apoptotic death of vascular smooth muscle cells (VSMCs). Integral disturbances lead to less organization within the aneurysm wall and fewer distinct layers. Simultaneously, MMP activation has been found to facilitate flow-induced internal elastic lamina (IEL) fragmentation. Vascular smooth muscle cells (VSMCs), mainly found in the media layer, are recognized as major producers of matrix in the vessel wall. Upon endothelial injury, intimal thickening occurs as VSMCs migrate into the intima and proliferate. Phenotypic transformation is seen in these migrated VSMCs as environmental change induces a switch from a contractile phenotype to a synthetic pro-inflammatory matrix remodeling phenotype in these cells. Endothelial cells are also affected by the hemodynamic insult. As blood flows, mechanical stimulus has notable effects on the cells of the vascular system. Consequently, IAs develop in vessel regions exposed to high hemodynamic stress such as arterial bifurcations and sharp angles. Experimentally, endothelial cells respond to hemodynamic stress with the up-regulation of the inflammatory mediator, prostaglandin E receptor 2 (EP2), during the formation of cerebral aneurysms. When shear stress was applied to primary endothelial cells, EP2 was found to be up-regulated. The stimulation of EP2 in primary endothelial cells also led to the activation of the transcription factor NF-B, a well-studied transcriptional mediator of inflammation in IA. As cerebral vessel walls undergo change during aneurysm development, the formation of new vessels, angiogenesis, also contributes to aneurysmal progression. Angiogenesis indirectly advances the inflammatory process of aneurysm progression by aiding in the delivery of inflammatory cells to vessel walls. Human and animal studies have both shown that inflammatory cells and mediators are involved in IA pathogenesis. A number of these inflammatory cells and mediators are highlighted in this section, with a special focus on the most recent investigation. T cells and macrophage infiltration have been found to be associated with human cerebral aneurysm rupture. Certain proteinases secreted by macrophages have been found to be involved in the vascular remodeling of aneurysm formation. Further connection has been found between macrophage presence and aneurysm rupture. The role of the inflammatory mediators, chemokines, has been studied in aneurysm formation. These data indicate that inflammatory cells are being actively recruited to the aneurysm wall as a result of high chemokine levels, further contributing to IA formation and eventual rupture. Intensive investigation has implicated the inflammation in the complex pathophysiological processes that underlie IA development, progression, and rupture.

• #1

  https://journals.lww.com/neur/fulltext/2017/65040/molecular_mechanisms_of_the_intracranial_aneurysms.10.aspx

  The expression level of each exon is different. […] ANRIL regulates CDKN2A/B in a cell-type specific mode. […] Cell cycle regulation has been shown to be an essential mechanism in the cardiovascular disease development. […] The cerebral vessels lack an external elastic lamina, making them more vulnerable to hemodynamic shear stresses. […] Loss of CDKN2B promotes p53-dependent SMC apoptosis and abdominal aortic aneurysm (AAA) formation, independent of changes in inflammatory immune cells. […] Increased p16INK4a expression mediates the inhibition of SMC proliferation by peroxisome proliferator-activated receptor (PPAR) , and p16INK4a deficiency enhances SMC proliferation and intimal hyperplasia in a carotid arterial-injury mouse model. […] The expression of CDKN2A is downregulated in ruptured IAs than in unruptured IAs.

• #1 The genetics of intracranial aneurysms | Journal of Human Genetics

  https://www.nature.com/articles/jhg200689

  Even though the etiology of IA formation is mostly unknown, several studies support a certain role of genetic factors. […] The identification of susceptible genes may lead to the understanding of the mechanism of formation and rupture and possibly lead to the development of a pharmacological therapy. […] Even though genetic factors are thought to play an important role in the pathogenesis of IA in addition to the well-published environmental factors, only recent progress in molecular genetics has enabled us to investigate the possible genetic determinants of this disease. […] Therefore, multiple genetic susceptibilities are considered to act together in the etiology of IA. […] The exact etiology of IA formation remains unclear. […] Aside from genetic factors, environmental factors such as hypertension, smoking and alcohol intake are related to the pathogenesis and eventual rupture of IAs. […] A single gene disorder does not seem to be involved, and a complex etiology involving multiple loci is proposed. […] Identification of predisposing genes may lead to a better understanding of the mechanism of IA formation.

• #1 Cerebral Aneurysm: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1161518-overview

  Environmental stressors, such as hypertension, have been associated with the presence of multiple aneurysms. A familial inheritance pattern has been noted in fewer than 2% of intracranial aneurysms. […] Dolichoectatic aneurysms of proximal vessels most likely have an arteriosclerotic etiology. These tortuous, elongated dilatations devoid of a true aneurysmal neck frequently contain laminated thrombus. Although aneurysmal SAH may occur, these lesions typically exert mass effects on adjacent parenchyma, with brainstem compression and cranial neuropathies, or result in obstruction of cerebrospinal fluid (CSF) outflow or distal thromboembolic sequelae. […] Infectious aneurysms typically are situated in distal branches of the middle cerebral artery (MCA; 7580% of cases), reflecting the embolic origin of these lesions. Cardioembolism of septic material complicates the course of 4% of patients with subacute bacterial endocarditis and may affect other patients with congenital heart disease and right-to-left shunts. Direct extension from lumen to adventitia of septic emboli containing Streptococcus viridans or Staphylococcus aureus (ie, the most common pathogens) may lead to degradation and aneurysm formation. Alternatively, diffuse infiltration from the periphery to the lumen may occur in the setting of meningitis, exemplified by aneurysms of the basal circulation associated with fungal infections. Infectious aneurysms are frequently multiple (20%) and have a greater propensity to bleed than other aneurysms.

• #1 Cerebral Aneurysm: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1161518-overview

  The development of cerebral aneurysms remains a controversial topic. A multifactorial etiology is most likely, reflecting the interaction of environmental factors, such as atherosclerosis or hypertension, and a congenital predisposition associated with various vascular abnormalities. Abnormalities of the internal elastic lamina may be congenital or degenerative. Multiple conditions have been associated with cerebral aneurysms; they include the following: Autosomal dominant inherited polycystic kidney disease, Fibromuscular dysplasia, Arteriovenous malformations, Osler-Weber-Rendu syndrome, Coarctation of the aorta, Other vascular anomalies, Moyamoya syndrome, Marfan syndrome, Ehlers-Danlos syndrome, type IV, Other collagen type III disorders, Pseudoxanthoma elasticum, Alpha1-antitrypsin deficiency, Systemic lupus erythematosus, Sickle cell anemia, Bacterial endocarditis, Fungal infections, Neurofibromatosis type 1, Tuberous sclerosis.

• #1 Dissecting the Genetic Architecture of Intracranial Aneurysms | medRxiv

  https://www.medrxiv.org/content/10.1101/2023.07.30.23293390v1.full-text

  We identified five novel loci association with IA, increasing the number of known susceptibility loci to 22. […] Taken together, our findings suggest that an intrinsic deficit in matrix production and vascular integrity may drive IA pathogenesis independent of systemic hypertension and smoking exposure. […] Our candidate causal gene set and PheWAS observations highlight directional discordance of many IA susceptibility loci with blood pressure and atherosclerosis. […] Together these data suggest that shared causal pathways seen in IA and other cardiovascular traits may result in divergent phenotypic consequences. […] Therefore, despite considerable genetic overlap with atherosclerosis and hypertension, we hypothesize that targeted IA therapeutics augmenting extracellular matrix production and vascular wall stability will provide the most utility for IA treatment or prevention. […] Our results suggest that focusing on SMC biology is likely to be particularly key for understanding IA pathologic mechanisms and identifying novel therapies.

• #1

  https://journals.lww.com/neur/fulltext/2017/65040/molecular_mechanisms_of_the_intracranial_aneurysms.10.aspx

  Long noncoding ribonucleic acids (RNAs) are important regulators of gene expression. Antisense noncoding RNA in the INK4 locus (ANRIL), which was coded on the Chr9p21.3 loci, participates in the pathogenesis of tumor, coronary artery disease, type 2 diabetes mellitus, and other diseases. A genome-wide association study indicated ANRIL to be a candidate gene that may lead to the development of an intracranial aneurysm (IA) formation. However, the detailed molecular mechanisms are unknown and have not been studied. […] Through reviewing the molecular mechanisms responsible for the development of IA and the regulation pathway of ANRIL, this paper presents four possible molecular mechanisms that may be responsible for the influence of ANRIL on the development of IAs, that is, cell cycling, Krppel-like factor 2 (KLF2), caspase recruitment domain family member 8, and retinoid metabolism. ANRIL may become a molecular marker or therapeutic target of IA in the future.

• #1 Cerebral Aneurysm: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1161518-overview

  Cerebral aneurysms are pathologic focal dilatations of the cerebrovasculature that are prone to rupture. These vascular abnormalities are classified by presumed pathogenesis. Saccular, berry, or congenital aneurysms constitute 90% of all cerebral aneurysms and are located at the major branch points of large arteries. Dolichoectatic, fusiform, or arteriosclerotic aneurysms are elongated outpouchings of proximal arteries that account for 7% of all cerebral aneurysms. Infectious or mycotic aneurysms are situated peripherally and comprise 0.5% of all cerebral aneurysms. Other peripheral lesions include neoplastic aneurysms, rare sequelae of embolized tumor fragments, and traumatic aneurysms. Traumatic injury also may result in dissecting aneurysms in proximal vessels. Microaneurysms of small perforating vessels may result from hypertension.

• #1 Intracranial aneurysm – Wikipedia

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

  Generally, aneurysms larger than 7 mm in diameter should be treated because they are prone for rupture. […] Saccular aneurysms are almost always the result of hereditary weaknesses in blood vessels and typically occur within the arteries of the circle of Willis. […] Saccular aneurysms tend to have a lack of tunica media and elastic lamina around their dilated locations (congenital), with a wall of sac made up of thickened hyalinized intima and adventitia.

• #1 Subarachnoid Hemorrhage: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1164341-overview

  The probability of rupture is related to the tension on the aneurysm wall. The law of La Place states that tension is determined by the radius of the aneurysm and the pressure gradient across the wall of the aneurysm. Thus, the rate of rupture is directly related to the size of the aneurysm. Aneurysms with a diameter of 5 mm or less have a 2% risk of rupture, whereas 40% of those with a diameter of 6-10 mm have already ruptured upon diagnosis. […] Although hypertension has been identified as a risk factor for aneurysm formation, the data with respect to rupture are conflicting. However, certain hypertensive states, such as those induced by use of cocaine and other stimulants, clearly promote aneurysm growth and rupture earlier than would be predicted by the available data. […] Brain injury from cerebral aneurysm formation can occur in the absence of rupture. Compressive forces can cause injury to local tissues and/or compromise of distal blood supply (mass effect).

• #1 Aneurysm | Better Health Channel

  https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/aneurysm

  An aneurysm is an abnormal swelling or bulge in the wall of a blood vessel, such as an artery. […] Aneurysms can occur anywhere throughout the circulatory system, but most commonly develop along the aorta (the bodys main artery that runs the length of the trunk) and in blood vessels of the brain. […] Aneurysms are potentially fatal if they rupture. […] It begins as a weak spot in the blood vessel wall, which balloons out of shape over time by the force of the pumping blood. […] Usually, aneurysms develop at the point where a blood vessel branches, because the fork is structurally more vulnerable. […] Some of the causes of aneurysms include: a weakness in the blood vessel wall that is present from birth (congenital aneurysm), high blood pressure (hypertension) over many years resulting in damage and weakening of blood vessels, fatty plaques (atherosclerosis) resulting in a weakness of the blood vessel wall, inherited diseases that may result in weaker than normal blood vessel walls, trauma, such as a crush injury to the chest, the sexually transmitted infection (STI) syphilis, if untreated, targeting the aorta and weakening its walls, polycystic kidney disease increasing the risk of cerebral aneurysm, very occasionally, an infection targeting and weakening a section of blood vessel.

• #1

  https://www.nhs.uk/conditions/brain-aneurysm/causes/

  Brain aneurysms are caused by a weakness in the walls of blood vessels in the brain. There are several reasons why this may happen, although an exact cause isn’t always clear. […] Most aneurysms develop at the points where the blood vessels divide and branch off, as these areas are often weaker. […] Exactly why smoking increases the risk of brain aneurysms is unclear. It may be that the harmful substances in tobacco smoke damage the walls of your blood vessels. […] High blood pressure can place increased pressure on the walls of the blood vessels inside the brain, potentially increasing your chances of developing an aneurysm. […] This may be because the walls of the blood vessels are weakened over time by the constant pressure of blood flowing through them. […] Oestrogen is thought to help maintain the elasticity of the blood vessels.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Why-are-Women-More-Likely-to-have-Brain-Aneurysms-Compared-to-Men.aspx

  A brain aneurysm is a diseased or abnormal dilatation of the cerebral arteries at a weak spot. These typically thin-walled aneurysmal sacs of blood may continue to enlarge because of the force of the arterial pulsatile flow. A ruptured aneurysm leads to a subarachnoid hemorrhage, an SAH. […] This has prompted the hypothesis that sex hormones are involved in the formation of aneurysms. This may be the reason, some say, that women are protected against aneurysms in their reproductive years, but the incidence rises after menopause. […] it is important to understand the process of aneurysm formation because alterations in this process may be responsible for the increased representation in women. […] Hemodynamic stress occurs due to the turbulent flow of blood along the brains blood vessels. The vibrations of turbulent flow and the collagen weakening cause the internal elastic lamina of the artery to weaken over time.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Why-are-Women-More-Likely-to-have-Brain-Aneurysms-Compared-to-Men.aspx

  In addition, inflammation mediated by the T lymphocytes and macrophages may cause the collagen to break down. All these factors work together to prompt the formation and growth of an aneurysm. […] Several mechanisms have been put forward to explain why females should be more vulnerable to the formation of cerebral aneurysms. […] Estrogen effects are thought to be mediated by receptors. In female rats, the cerebral blood vessels show a wealth of estrogen receptors alpha (ER-) on both the smooth muscle and the endothelium cells. […] The first theory is that the arteries of the brain are weaker in older women because of reduced estrogen stimulation after menopause. This may reduce the collagen content in the vessel wall. […] Hemodynamic forces could induce the formation of aneurysms by increasing wall shear stress (WSS). This could damage the endothelial lining, inducing remodeling changes in the vascular endothelium.

• #1 PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis | Stroke and Vascular Neurology

  https://svn.bmj.com/content/10/2/e003076

  Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. […] Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms. […] Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing. […] This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.

• #1 PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis | Stroke and Vascular Neurology

  https://svn.bmj.com/content/10/2/e003076

  Identifying PSMA4 and PRCP as potential drug targets in cerebral aneurysms may pave the way for targeted therapies, influencing future research and clinical practices in preventing or treating intracranial aneurysm rupture. […] The results suggest that PSMA4 and IA likely share a causal variant within the PSMA4 locus, and PRCP and SAH likely share a causal variant within the PRCP locus. […] Our study not only validated the relationship between PSMA4 and IA but also revealed its relationship with SAH. […] Confirming the involvement of PSMA4 in IA and discovering its role in SAH enhances our understanding of its contribution to these conditions, emphasising its potential role in their development or progression. […] Encouragingly, our two-sample MR analysis demonstrated that elevated PRCP gene expression in the blood is causally associated with a lower risk of SAH (IA rupture).

• #1

  https://grantome.com/grant/NIH/R01-NS111119-01A1

  Endothelial dysfunction is highlighted as an early marker of vascular abnormality preceding cerebral aneurysm formation, but the molecular events behind this transformation remain unclear. […] Our preliminary data indicate that IL-2 is expressed in human cerebral aneurysm tissue and induces a phenotypic switch in endothelial cell (EC) function from the maintenance of vasomotor activity, to promotion of inflammation and matrix remodeling. […] Collectively this preliminary data suggests a vital role of the IL-2/mTOR pathway in aneurysm progression. […] The central hypothesis of this proposal is that IL-2/mTOR inhibition promotes repopulation of EC and decreases inflammation, which halts aneurysm progression and promotes vascular healing. […] The proposed research is innovative in that successful completion of this project will determine the events behind EC dysfunction which lead to aneurysm progression and will help develop novel minimally invasive therapeutic strategies for aneurysm obliteration. […] Upon conclusion of this study, we will have an understanding of the role of IL-2 activated mTOR in endothelial cell dysfunction leading to aneurysm formation, progression and rupture.

• #1 Barrow Study Shows How Nicotine May Promote Brain Aneurysm Rupturebarrow facility icon

  https://www.barrowneuro.org/about/news-and-articles/research/nicotine-brain-aneurysm-rupture/

  While studies have shown that cigarette smoking increases the risk of rupturing a brain aneurysm, the underlying molecular and cellular processes have not been well understood. […] A recent Barrow Neurological Institute study published in Stroke has identified how nicotine may enable the rupture of these blood vessel abnormalities under certain circumstances. […] “In terms of mechanism, we found that nicotine promotes aneurysmal rupture through the activation of the α7 nicotinic receptor,” said Dr. Tomoki Hashimoto, who collaborated on the study with Dr. Michael Lawton. […] Previous studies have found that nicotine’s interaction with the α7 nicotinic receptor on blood vessel walls promotes inflammation and angiogenesis, or the formation of new blood vessels. […] Barrow researchers hypothesized that this interaction contributes to the pathophysiology of brain aneurysms, or the functional changes in the body associated with brain aneurysms.

• #1 PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis | Stroke and Vascular Neurology

  https://svn.bmj.com/content/10/2/e003076

  This genetic evidence supports the development of targeted drugs to prevent IA ruptures, addressing a critical gap in current medical interventions. […] This suggests that PRCP prevents IA rupture by fostering endothelial cell proliferation for vessel repair. […] Considering oxidative stress as a potential mechanism for aneurysm rupture, it is reasonable to speculate that PRCP may prevent IA rupture through its antioxidant effects. […] In conclusion, our study underscores the potential of targeting PSMA4 to mitigate the risk of IA and SAH. Additionally, our findings highlight PRCP as a robust target for preventing IA rupture, supported by diverse omics data.

• #2 Intracranial aneurysm – Wikipedia

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

  An intracranial aneurysm, also known as a cerebral aneurysm, is a cerebrovascular disorder characterized by a localized dilation or ballooning of a blood vessel in the brain due to a weakness in the vessel wall. […] The risk of rupture varies with the size and location of the aneurysm, with those in the posterior circulation being more prone to rupture. […] Saccular aneurysms are the most common type and can result from various risk factors, including genetic conditions, hypertension, smoking, and drug abuse. […] Aneurysm means an outpouching of a blood vessel wall that is filled with blood. Aneurysms occur at a point of weakness in the vessel wall. This can be because of acquired disease or hereditary factors. The repeated trauma of blood flow against the vessel wall presses against the point of weakness and causes the aneurysm to enlarge.

• #2 The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture in: Neurosurgical Focus Volume 47 Issue 1 (2019) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/47/1/article-pE11.xml

  Recently, considerable research has focused on the relationship between hemodynamic stressors and aneurysm pathogenesis. From a mathematical and biophysical standpoint, aneurysm morphology and evolution over time is highly complex due to the heterogeneous nature of fluid mechanics. Complicating matters even further is the living nature of blood vessels, i.e., mechanical stimuli are transduced into biological signals, triggering inflammatory cascades and, ultimately, a wide range of transcriptional and signaling changes that lead to vascular wall remodeling. […] The effect of arterial WSS on aneurysm pathogenesis has been the subject of extensive study. Shear stress is composed of the tangential, frictional forces that exist between blood and the stationary vessel wall. […] WSS is an important parameter in animal aneurysm formation models. Gao et al. identified high WSS as an important factor in aneurysm formation in a rabbit model.

• #2 High Wall Shear Incites Cerebral Aneurysm Formation and Low Wall Shear Stress Propagates Cerebral Aneurysm Growth | Shantha Kumar | Journal of Neurology Research

  https://www.neurores.org/index.php/neurores/article/view/749/718

  High shear stress in arterial branch points and bifurcations coincides with histological markers of nascent CA formation. […] Low wall shear stress increases the initial proinflammatory effect already present in the vasculature, which furthers the formation of cerebral aneurysms. […] The primary hemodynamic cause of CA growth, formation, and rupture is wall shear stress (WSS). […] High WSS commonly develops at arterial vascular branch points and arterial bifurcations, where blood flow suddenly changes from the steady uniform laminar pattern into a more chaotic turbulent pattern exerting greater tension on the vascular wall. […] Flow acceleration at bifurcation points produces a hemodynamic environment characterized by high WSS which triggers initiation of aneurysmal dilation. […] Low levels of WSS evoke a proinflammatory endothelial cell phenotype leading to aneurysmal growth, progression, and rupture.

• #2 The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture in: Neurosurgical Focus Volume 47 Issue 1 (2019) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/47/1/article-pE11.xml

  Although aneurysm formation has been clearly linked to regions of high WSS, the impact of the hemodynamic environment on aneurysm enlargement and rupture is less certain. Conflicting studies have found both high and low WSS to be related to aneurysm growth and eventual rupture. […] The high-stress theory asserts that elevation of maximum WSS causes endothelial injury and initiates processes of wall remodeling and degeneration. […] Conversely, the low-stress theory states that stagnation of blood within the aneurysm leads to red blood cell aggregation and buildup of platelets and leukocytes. […] Meng et al. proposed that low WSS (as well as high oscillatory shear index [OSI]) leads to a proinflammatory endothelial cell phenotype and increased inflammatory cell infiltration, matrix metalloproteinase (MMP) production, SMC proliferation and migration, and thrombus formation.

• #2 Underlying mechanism of hemodynamics and intracranial aneurysm | Chinese Neurosurgical Journal | Full Text

  https://cnjournal.biomedcentral.com/articles/10.1186/s41016-021-00260-2

  In modern society, subarachnoid hemorrhage, mostly caused by intracranial aneurysm rupture, is accompanied by high disability and mortality rate, which has become a major threat to human health. […] In recent years, more and more studies focus on the relationship between hemodynamics and intracranial aneurysm. Under the physiological condition, the mechanical force produced by the stable blood flow in the blood vessels keeps balance with the structure of the blood vessels. When the blood vessels are stimulated by the continuous abnormal blood flow, the functional structure of the blood vessels changes, which becomes the pathophysiological basis of the inflammation and atherosclerosis of the blood vessels and further promotes the occurrence and development of the intracranial aneurysm. […] At present, many studies have confirmed that abnormal hemodynamics, as an initiating factor, is involved in the occurrence and development of IA.

• #2 Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

  https://www.oaepublish.com/articles/2347-8659.154433

  Intracranial aneurysms are a life-threatening cerebrovascular pathology with a probability of spontaneous rupture. Recent investigation has reinforced inflammation’s role in the pathophysiological process of cerebral aneurysms. The majority of evidence from intensive investigation has implicated a mounting inflammatory response during the aneurysm pathogenesis. Hemodynamic insult is considered to be one of the first steps in activating the cerebral vessel walls’ inflammatory response. Upon the hemodynamic insult, this balance is perturbed, leading to vessel wall weakening. Dilation results, as extracellular matrix is degraded by increased levels of matrix metalloproteinases (MMP) compounded by concomitant apoptotic death of vascular smooth muscle cells (VSMCs). Integral disturbances lead to less organization within the aneurysm wall and fewer distinct layers. Simultaneously, MMP activation has been found to facilitate flow-induced internal elastic lamina (IEL) fragmentation. Vascular smooth muscle cells (VSMCs), mainly found in the media layer, are recognized as major producers of matrix in the vessel wall. Upon endothelial injury, intimal thickening occurs as VSMCs migrate into the intima and proliferate. Phenotypic transformation is seen in these migrated VSMCs as environmental change induces a switch from a contractile phenotype to a synthetic pro-inflammatory matrix remodeling phenotype in these cells. Endothelial cells are also affected by the hemodynamic insult. As blood flows, mechanical stimulus has notable effects on the cells of the vascular system. Consequently, IAs develop in vessel regions exposed to high hemodynamic stress such as arterial bifurcations and sharp angles. Experimentally, endothelial cells respond to hemodynamic stress with the up-regulation of the inflammatory mediator, prostaglandin E receptor 2 (EP2), during the formation of cerebral aneurysms. When shear stress was applied to primary endothelial cells, EP2 was found to be up-regulated. The stimulation of EP2 in primary endothelial cells also led to the activation of the transcription factor NF-B, a well-studied transcriptional mediator of inflammation in IA. As cerebral vessel walls undergo change during aneurysm development, the formation of new vessels, angiogenesis, also contributes to aneurysmal progression. Angiogenesis indirectly advances the inflammatory process of aneurysm progression by aiding in the delivery of inflammatory cells to vessel walls. Human and animal studies have both shown that inflammatory cells and mediators are involved in IA pathogenesis. A number of these inflammatory cells and mediators are highlighted in this section, with a special focus on the most recent investigation. T cells and macrophage infiltration have been found to be associated with human cerebral aneurysm rupture. Certain proteinases secreted by macrophages have been found to be involved in the vascular remodeling of aneurysm formation. Further connection has been found between macrophage presence and aneurysm rupture. The role of the inflammatory mediators, chemokines, has been studied in aneurysm formation. These data indicate that inflammatory cells are being actively recruited to the aneurysm wall as a result of high chemokine levels, further contributing to IA formation and eventual rupture. Intensive investigation has implicated the inflammation in the complex pathophysiological processes that underlie IA development, progression, and rupture.

• #2 The Role of NF-κB in Intracranial Aneurysm Pathogenesis: A Systematic Review

  https://www.mdpi.com/1422-0067/24/18/14218

  The expression of these pro-inflammatory markers and MMPs is regulated by NF-κB transcription activity. Experimental studies have shown that NF-κB activation increases the expression of these markers, and by blocking NF-κB activation, the expression of these inflammatory markers and MMPs could be reduced. […] NF-κB activation increases the transcription and protein expression of inflammatory markers and MMPs. Higher mRNA expression, protein levels, and concentrations of pro-inflammatory markers in serum and IA walls have been reported in clinical and experimental animal studies. The mRNA and protein expression of these inflammatory markers were lowered by pharmacological treatments and genetic manipulations, which also reduced the incidence of IA formation, growth, and rupture. […] Furthermore, blocking NF-κB expression and activation reduced the expression of pro-inflammatory markers including IL-1β, MCP-1, and VCAM-1.

• #2 New Pathophysiological Considerations on Cerebral Aneurysms

  https://neurointervention.org/journal/view.php?number=236

  This review deals with the basic knowledge and advanced concepts underlying the pathophysiology of cerebral aneurysms. […] Although the exact pathogenesis of cerebral aneurysm formation, growth, and rupture remains to be established, extracellular matrix defects and degeneration, hemodynamic stress, and inflammatory responses have been suggested as key components leading to structural fragility in the arterial wall. […] The perturbations of structural component are specified in Table 1. […] The longevity of elastin generated in early embryogenesis is similar to the human life span, and rarely experiences a wear and tear process. […] Once extracellular matrix defects or degradation take place, the disease course may not be restored. […] An imbalance between MMPs and their inhibitors contributes to initiation and progression of cerebral aneurysms.

• #2 Inflammation mediates the pathogenesis of cerebral aneurysm and becomes therapeutic target

  https://www.oaepublish.com/articles/2347-8659.154381

  The treatment of cerebral aneurysms (CAs) is of social importance, because poor outcomes result in subarachnoid hemorrhages after rupture. […] Recent studies using human samples have revealed the presence of inflammatory responses in lesions and also the possible correlation of inflammation with CA progression or rupture. Furthermore, experimental studies using animal models of CAs have supported the notion from human studies and have clarified the crucial contribution of inflammation to the pathogenesis. […] Over the past couple of decades, a large number of studies have examined the underlying mechanism of CA formation, progression and rupture by investigating human CA specimens. These series of studies have identified the presence of the inflammatory responses in CA lesions and have suggested the role of the inflammatory processes in the pathogenesis of CAs.

• #2 Pharmaceutical Modulation of Intracranial Aneurysm Development and Rupture

  https://www.mdpi.com/2077-0383/13/11/3324

  Aneurysm development depends on a variety of factors including endothelial cell (EC) dysfunction, vessel wall shear stress (WSS), vascular smooth muscle cell (VSMC) dysfunction, extracellular matrix (ECM) remodeling, and immune cell infiltration. […] WSS has been reported to be higher at branch points in the Circle of Willis where aneurysms frequently develop. […] Mechanical stress can upregulate the expression of nuclear factor-kB (NF-kB) which may further induce the expression of cell adhesion molecules, increase chemokines such as monocyte chemoattractant protein-1 (MCP-1), and downregulate important contractile proteins. […] The resultant endothelial and VSMC dysfunction can lead to apoptosis and immune cell infiltration, creating an ideal inflammatory microenvironment for aneurysm formation.

• #2 The Role of NF-κB in Intracranial Aneurysm Pathogenesis: A Systematic Review

  https://www.mdpi.com/1422-0067/24/18/14218

  The pathophysiology of IAs is complex. Although many factors play together in the formation, progression, and rupture of IAs, the research hitherto suggests that inflammation heavily contributes to IAs from formation to rupture. The endothelial dysfunction, smooth muscle cells (SMCs) phenotypic switching, infiltration and accumulation of inflammatory cells in the arterial walls, and the expression and release of pro-inflammatory cytokines such as interleukin (IL) -1β, and tumor necrosis factor-alpha (TNF-α), chemokines such as monocyte chemoattractant protein-1 (MCP-1), and IL-8, cell adhesion molecules, namely, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and extracellular matrix remodeling proteinases such as MMPs including MMP-2 and MMP-9 have been implicated in IA formation and rupture.

• #2 Pharmaceutical Modulation of Intracranial Aneurysm Development and Rupture

  https://www.mdpi.com/2077-0383/13/11/3324

  Central to aneurysm development is NF-kB, a mediator of inflammation. […] Several clinical studies have demonstrated greater expression of NF-kB protein in the vessel wall of IAs compared to normal vascular tissue. […] Thus, in addition to the aforementioned mechanisms of IA pathogenesis, NF-kB is an inflammatory mediator that may be a potential target for drug-based therapy. […] In summary, aneurysms develop when shear stress at branch points in arterial circulation leads to the upregulation of maladaptive genes, such as NF-kB. […] Consequently, the increased expression of chemokines and cell adhesion molecules leads to the development of an inflammatory local environment. These processes together can cause the degradation of important structural components of the vessel wall, including vascular smooth muscle and extracellular matrix.

• #2

  https://scholars.duke.edu/individual/pub1506549

  Vascular smooth muscle cells (SMC) maintain significant plasticity. Following environmental stimulation, SMC can alter their phenotype from one primarily concerned with contraction to a pro-inflammatory and matrix remodeling phenotype. This is a critical process behind peripheral vascular disease and atherosclerosis, a key element of cerebral aneurysm pathology. […] Evolving evidence demonstrates that SMCs and phenotypic modulation play a significant role in cerebral aneurysm formation and rupture. […] Pharmacological alteration of smooth muscle cell function and phenotypic modulation could provide a promising medical therapy to inhibit cerebral aneurysm progression. […] This study reviews vascular SMC function and its contribution to cerebral aneurysm pathophysiology.

• #2

  https://journals.lww.com/neur/fulltext/2017/65040/molecular_mechanisms_of_the_intracranial_aneurysms.10.aspx

  Silencing of ANRIL reduces the proliferation of vascular SMCs, which might be the result of premature senescence, an important mechanism in endothelial dysfunction and the SMC conversion to a proinflammatory phenotype. […] IAs are predominately located at places that incur endothelial damage. […] Proliferation of fibroblasts that protect against IAs is also reduced by silencing of ANRIL. […] KLF2 plays an anti-inflammatory role in multiple cell types. […] Angiogenesis within the aneurysm wall is considered to regulate aneurysm wall remodeling and is suspected to have a critical role in aneurysm formation and rupture. […] Retinoids may be associated with IA by migration and apoptosis of SMCs. […] The lack of vitamin A leads to impaired immunity, anemia, and mortality. […] The mechanisms by which ANRIL affects so many pathologically different diseases is of major concern. […] Research in the future will unequivocally establish the role of ANRIL as a biomarker of IAs or as a therapeutic target in which interference with the ANRIL metabolic pathway may lead to regression of IAs.

• #2 Subarachnoid Hemorrhage: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1164341-overview

  The occurrence of aneurysms in children indicates the role of intrinsic vascular factors. A number of disease states resulting in weakness of the arterial wall are associated with an increased incidence of berry aneurysms. […] Mechanisms and disease states associated with higher incidence of berry aneurysms include the following: Increased blood pressure: Fibromuscular dysplasia, polycystic kidney disease, aortic coarctation; Increased blood flow: Cerebral arteriovenous malformation (AVM); persistent carotid-basilar anastomosis; ligated, aplastic, or hypoplastic contralateral vessel; Blood vessel disorders: Systemic lupus erythematosus (SLE), Moyamoya disease, granulomatous angiitis; Genetic disorders: Marfan syndrome, Ehlers-Danlos syndrome, Osler-Weber-Rendu syndrome, pseudoxanthoma elasticum, Klippel-Trenaunay-Weber syndrome; Congenital conditions: Persistent fetal circulation, hypoplastic/absent arterial circulation; Metastatic tumors to cerebral arteries: Atrial myxoma, choriocarcinoma, undifferentiated carcinoma; Infections: Bacterial, fungal.

• #2

  https://journals.lww.com/neur/fulltext/2017/65040/molecular_mechanisms_of_the_intracranial_aneurysms.10.aspx

  The four possible molecular mechanisms of ANRIL on the development of intracranial aneurysms include its influence on cell cycling, Krppel-like factor 2 (KLF2), caspase recruitment domain family member 8, and retinoid metabolism. […] With the advent of genome-wide association study (GWAS), it is frequently reported that the long noncoding RNA, antisense noncoding RNA in the INK4 locus (ANRIL), has a significant association with an IA. However, the detailed mechanism has not been clarified. This paper reviewed the previous studies and proposed a potential molecular mechanism that defines the role of ANRIL in the development of IAs. […] The linkage between ANRIL and IAs has been proved in a series of GWAS. […] The combined effects of the three loci showed a more than threefold increase than the effect of a single locus.

• #2 Intracranial Aneurysms: Current Evidence and Clinical Practice | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/0815/p601.html

  Intracranial aneurysms are classified as saccular, fusiform, or dissecting. Approximately 90 percent are saccular (berry aneurysms). Saccular aneurysms develop from defects in the muscular layer (tunica muscularis) of arteries. Alterations in the internal elastic membrane (lamina elastica interna) of cerebral arteries are thought to weaken vessel walls and render them less resistant to changes in intraluminal pressure. These changes most frequently develop at sites of vessel bifurcation, where blood flow is most turbulent and shear forces against the arterial wall are greatest. […] Saccular aneurysms most frequently form in first- and second-order arteries originating from the cerebral arterial circle (circle of Willis) at the base of the brain. Multiple aneurysms develop in 30 percent of affected patients. […] Dissecting aneurysms are the result of cystic medial necrosis or a traumatic tear of an artery. Like dissecting aneurysms elsewhere in the body (e.g., dissecting aortic aneurysms), they form as blood courses through a false lumen while the true lumen is collapsed upon itself.

• #2 < ?php wp_title( '|', true, 'right' ); ?>

  https://surgicalneurologyint.com/surgicalint-articles/ruptured-mycotic-cerebral-aneurysm-development-from-pseudoocclusion-due-to-septic-embolism/

  Cerebral mycotic aneurysms are rare sequelae of systemic infections that can cause profound morbidity and mortality with rupture. Direct bacterial extension and vessel integrity compromise from septic emboli have been implicated as mechanisms for formation of these lesions. […] The pathogenesis is related to the adherence of an embolus onto the vessel wall with subsequent direct bacterial extension and disruption of the underlying structures resulting in aneurysm formation. […] This defect in the vessel wall is induced by cytotoxic effects from the septic embolus, ischemic injury caused by occlusion of the vasa vasorum, and architectural breakdown of the media and adventitial layers caused by inflammatory response. […] Aneurysmal growth is promoted by repetitive arterial pulsation against the vulnerable, predisposed vessel wall.

• #2 New Pathophysiological Considerations on Cerebral Aneurysms

  https://neurointervention.org/journal/view.php?number=236

  Cerebral aneurysm is a common cerebrovascular disease that is sometimes complicated by rupture or an enlarged mass. […] The actual rupture rate is very low and the diagnostic and treatment modalities are expensive and invasive, which may lead to unnecessary costs and potential medical complications. […] This disproportionate situation is related to a poor understanding of the natural course and pathophysiology of cerebral aneurysms. […] Cerebral aneurysms may follow a variety of pathophysiological scenarios over their lifetime, from formation to growth and rupture. […] The disease course and the final outcome can differ depending on the timing and intensity of the pathological signals acting on the cerebral vessel wall. […] We should delineate a method of predicting the stability and risk of rupture of the lesion based on a comprehensive knowledge of the vessel wall integrity.

• #2 Subarachnoid Hemorrhage: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1164341-overview

  The probability of rupture is related to the tension on the aneurysm wall. The law of La Place states that tension is determined by the radius of the aneurysm and the pressure gradient across the wall of the aneurysm. Thus, the rate of rupture is directly related to the size of the aneurysm. Aneurysms with a diameter of 5 mm or less have a 2% risk of rupture, whereas 40% of those with a diameter of 6-10 mm have already ruptured upon diagnosis. […] Although hypertension has been identified as a risk factor for aneurysm formation, the data with respect to rupture are conflicting. However, certain hypertensive states, such as those induced by use of cocaine and other stimulants, clearly promote aneurysm growth and rupture earlier than would be predicted by the available data. […] Brain injury from cerebral aneurysm formation can occur in the absence of rupture. Compressive forces can cause injury to local tissues and/or compromise of distal blood supply (mass effect).

• #2

  https://www.nhs.uk/conditions/brain-aneurysm/causes/

  Brain aneurysms are caused by a weakness in the walls of blood vessels in the brain. There are several reasons why this may happen, although an exact cause isn’t always clear. […] Most aneurysms develop at the points where the blood vessels divide and branch off, as these areas are often weaker. […] Exactly why smoking increases the risk of brain aneurysms is unclear. It may be that the harmful substances in tobacco smoke damage the walls of your blood vessels. […] High blood pressure can place increased pressure on the walls of the blood vessels inside the brain, potentially increasing your chances of developing an aneurysm. […] This may be because the walls of the blood vessels are weakened over time by the constant pressure of blood flowing through them. […] Oestrogen is thought to help maintain the elasticity of the blood vessels.

• #2

  https://www.nhs.uk/conditions/brain-aneurysm/causes/

  In some cases, brain aneurysms are caused by weaknesses in the blood vessels present from birth. […] Cocaine can inflame the walls of the blood vessels and raise your blood pressure. The combination of these factors increases your risk of developing a brain aneurysm. […] Brain aneurysms can be more common in people with ADPKD, due to high blood pressure affecting the weakened blood vessel walls. […] This is because these conditions can sometimes cause weaknesses in the walls of your blood vessels.

• #2 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Why-are-Women-More-Likely-to-have-Brain-Aneurysms-Compared-to-Men.aspx

  The higher WSS in women could put them at higher risk of aneurysms along the ICA course. Even at the same blood pressure, therefore, the reduced vessel diameter in women relative to men in the proximal part of the ICA increases the chances of aneurysm formation in women. […] The size ratio, that is, the ratio of intracranial aneurysm diameter to vessel diameter increases the risk of rupture. Since women tend to have smaller blood vessel diameter, this increases their risk of aneurysmal rupture.

• #2 PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis | Stroke and Vascular Neurology

  https://svn.bmj.com/content/10/2/e003076

  Identifying PSMA4 and PRCP as potential drug targets in cerebral aneurysms may pave the way for targeted therapies, influencing future research and clinical practices in preventing or treating intracranial aneurysm rupture. […] The results suggest that PSMA4 and IA likely share a causal variant within the PSMA4 locus, and PRCP and SAH likely share a causal variant within the PRCP locus. […] Our study not only validated the relationship between PSMA4 and IA but also revealed its relationship with SAH. […] Confirming the involvement of PSMA4 in IA and discovering its role in SAH enhances our understanding of its contribution to these conditions, emphasising its potential role in their development or progression. […] Encouragingly, our two-sample MR analysis demonstrated that elevated PRCP gene expression in the blood is causally associated with a lower risk of SAH (IA rupture).

• #2 PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis | Stroke and Vascular Neurology

  https://svn.bmj.com/content/10/2/e003076

  This genetic evidence supports the development of targeted drugs to prevent IA ruptures, addressing a critical gap in current medical interventions. […] This suggests that PRCP prevents IA rupture by fostering endothelial cell proliferation for vessel repair. […] Considering oxidative stress as a potential mechanism for aneurysm rupture, it is reasonable to speculate that PRCP may prevent IA rupture through its antioxidant effects. […] In conclusion, our study underscores the potential of targeting PSMA4 to mitigate the risk of IA and SAH. Additionally, our findings highlight PRCP as a robust target for preventing IA rupture, supported by diverse omics data.

• #2 Barrow Study Shows How Nicotine May Promote Brain Aneurysm Rupturebarrow facility icon

  https://www.barrowneuro.org/about/news-and-articles/research/nicotine-brain-aneurysm-rupture/

  Using preclinical models developed in a Barrow laboratory, the researchers found that nicotine did significantly increase the aneurysm rupture rate. […] Their models also suggested that this occurs through actions on the α7 nicotinic receptors on smooth muscle cells in the walls of blood vessels and through the promotion of sustained angiogenesis and inflammation. […] When they used a substance known to block the α7 nicotinic receptor, it effectively abolished nicotine’s promotion of aneurysm rupture. […] “Smoking has long been associated with aneurysm formation and rupture, and our work in the Barrow Aneurysm and AVM Research Center demonstrates how nicotine is a powerful actor in this disease,” Dr. Lawton said. […] Dr. Hashimoto said the next step in this line of research is to investigate whether the α7 nicotinic receptor can be targeted in preclinical models without nicotine. […] The models in this study were not specifically designed to detect whether nicotine contributes to the formation of aneurysms, providing another research avenue.

• #2 The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture in: Neurosurgical Focus Volume 47 Issue 1 (2019) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/47/1/article-pE11.xml

  Despite not knowing the exact mechanism involved, a recent report by Cebral et al. supports the theory that different hemodynamic conditions are associated with different aneurysm phenotypes. […] Abnormal hemodynamics serves as a trigger for vascular modeling and the biochemical mechanisms that persist following the inciting stressor. […] In the presence of hemodynamic stressors, flow-dependent NO release inhibits the proliferation of VSMCs and can initiate apoptosis by activating caspase 3. […] The disappearance of the IEL is among the first histological changes observed during aneurysmal growth, leaving the adventitia as the only layer resisting transmural blood pressure. […] As imaging studies and computational modeling continue to improve, understanding of the hemodynamic role in cerebral aneurysm formation, growth, and rupture will increase.

• #2 The genetics of intracranial aneurysms | Journal of Human Genetics

  https://www.nature.com/articles/jhg200689

  Even though the etiology of IA formation is mostly unknown, several studies support a certain role of genetic factors. […] The identification of susceptible genes may lead to the understanding of the mechanism of formation and rupture and possibly lead to the development of a pharmacological therapy. […] Even though genetic factors are thought to play an important role in the pathogenesis of IA in addition to the well-published environmental factors, only recent progress in molecular genetics has enabled us to investigate the possible genetic determinants of this disease. […] Therefore, multiple genetic susceptibilities are considered to act together in the etiology of IA. […] The exact etiology of IA formation remains unclear. […] Aside from genetic factors, environmental factors such as hypertension, smoking and alcohol intake are related to the pathogenesis and eventual rupture of IAs. […] A single gene disorder does not seem to be involved, and a complex etiology involving multiple loci is proposed. […] Identification of predisposing genes may lead to a better understanding of the mechanism of IA formation.

• #2 Molecular Mechanisms of the Formation and Progression of Intracranial Aneurysms

  https://www.jstage.jst.go.jp/article/nmc/55/3/55_ra.2014-0337/_article

  Until recently, only a little was understood about molecular mechanisms of the development of an intracranial aneurysm (IA). […] Recent advancements over the last decade in the field of genetics and molecular biology have provided us a wide variety of evidences supporting the notion that chronic inflammation is closely associated with the pathogenesis of IA development. […] Researches in molecular biology using human samples and animal models have revealed the common pathway of the initiation, progression, and rupture of IAs. […] IA formation begins with endothelial dysfunction followed by pathological remodeling with degenerative changes of vascular walls. […] Medical treatments inhibiting inflammatory cascades in IA development are likely to prevent IA progression and rupture. […] Further clarification of molecular mechanisms of the formation and progression of IAs will shed light to the pathogenesis of IA development and provide insight into novel diagnostic and therapeutic strategies for IAs.

• #3 Brain aneurysm – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/brain-aneurysm/symptoms-causes/syc-20361483

  Experts think brain aneurysms form and grow because blood flowing through the blood vessel puts pressure on a weak area of the vessel wall. This can increase the size of the brain aneurysm. […] Brain aneurysms are caused by thinning artery walls. Aneurysms often form at forks or branches in arteries because those areas of the vessels are weaker. […] Several factors can cause weakness in an artery wall. These factors may increase the risk of a brain aneurysm or aneurysm rupture. […] There are some factors that make it more likely an aneurysm will rupture. They include having a large aneurysm, having aneurysms in certain locations, and having untreated high blood pressure. […] When a brain aneurysm ruptures, the bleeding usually lasts only a few seconds. However, the blood can cause direct damage to surrounding cells and can kill brain cells. It also increases pressure inside the skull.

• #3 Inflammation mediates the pathogenesis of cerebral aneurysm and becomes therapeutic target

  https://www.oaepublish.com/articles/2347-8659.154381

  Comprehensive gene expression analyses have revealed the induction of pro-inflammatory genes in lesions such as TNF- and the up-regulation of the inflammation-related pathways through bioinformatics analyses such as antigen processing, immune responses, and responses to outward stimuli, which indicated a significant contribution to the pathogenesis of CAs. […] Recent experimental studies mainly using animal models of CAs have clarified the involvement of inflammatory responses in the pathogenesis of CA formation and progression and have supported the notion that inflammation in arterial walls contributes to the pathogenesis in human cases. […] Nuclear factor-kappa B (NF-B) is a master transcription factor regulating the induction of various pro-inflammatory genes through the activation of responses to nociceptive stimuli.

• #3 Brain Aneurysm: Symptoms, Causes, Risk Factors

  https://www.healthline.com/health/aneurysm-in-the-brain

  Some aneurysms will never rupture. However, there are also risk factors that can increase the chance of a ruptured aneurysm. […] Risk of rupture is raised in brain aneurysms that are large, have grown larger over time, located in certain arteries, specifically the posterior communicating arteries and the anterior communicating arteries. […] Additionally, some events may encourage an aneurysm to rupture. An older 2011 study assessed the relative risk of certain events in 250 individuals who had previously experienced a ruptured aneurysm. It found that the following were associated with the rupture of an existing aneurysm: excessive exercise, coffee or soda consumption, straining during bowel movements, nose blowing, experiencing intense anger, being startled, sexual intercourse. […] Treatment for a brain aneurysm can vary based on several factors, including the location and size of the aneurysm, your age and overall health, your personal and family medical history, whether the aneurysm is at risk of rupturing or has already ruptured.

• #3 PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis | Stroke and Vascular Neurology

  https://svn.bmj.com/content/10/2/e003076

  This genetic evidence supports the development of targeted drugs to prevent IA ruptures, addressing a critical gap in current medical interventions. […] This suggests that PRCP prevents IA rupture by fostering endothelial cell proliferation for vessel repair. […] Considering oxidative stress as a potential mechanism for aneurysm rupture, it is reasonable to speculate that PRCP may prevent IA rupture through its antioxidant effects. […] In conclusion, our study underscores the potential of targeting PSMA4 to mitigate the risk of IA and SAH. Additionally, our findings highlight PRCP as a robust target for preventing IA rupture, supported by diverse omics data.

Zobacz więcej