Materiały źródłowe

• #1 Hereditary Hemorrhagic Telangiectasia (HHT) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578186/

  Hereditary hemorrhagic telangiectasias (HHT) is an autosomal dominant bleeding disorder caused by malformed vessels. The condition manifests as telangiectasias affecting the skin and mucosa and arteriovenous malformations involving organs like the lung, brain, and liver. This activity reviews the pathophysiology of the disease and emphasizes the importance of an interprofessional teams approach to evaluating and treating patients with this condition. […] HHT is an autosomal dominant disorder affecting blood vessels within multiple organ systems. The condition is suspected of haploinsufficiency, where 1 functional gene copy cannot produce the required protein to preserve function. […] Pathogenesis of HHT is primarily due to the gene mutations (endoglin, ACVRL1, and SMAD4) that affect the endothelial cell receptors of the TGF-B superfamily. A mutation in these receptors prevents downstream signaling and disrupts angiogenesis, promoting a disorganized cytoskeleton and dysfunctional remodeling of the vascular endothelium. As a result, these vessels lose elasticity and remain chronically dilated.

• #2 Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9457069/

  Hereditary hemorrhagic telangiectasia (HHT) is an inherited disease related to an alteration in angiogenesis, manifesting as cutaneous telangiectasias and epistaxis. […] This disease is caused, in approximately 90% of cases, by a heterozygous mutation of the endoglin gene (ENG) or the activin-like receptor kinase 1, called ALK1 (also known as ACVRL1), characterized by an autosomal dominant inheritance pattern. […] The relationship between the endothelium and affected genes in HHT is based on the positive regulation of angiogenesis by ENG and ACVRL1, a process in which the pathways of endothelial cell migration and proliferation are central. […] The haploinsufficiency model in HHT is the most accepted theory for the pathogenesis of disease development. […] This lack of protein expression results in impairment on routes via ENG or ACVRL1 that normally enhances endothelial migration and proliferation.

• #3

  https://www.jci.org/articles/view/176379

  Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder with highly variable expressivity, affecting up to 1 in 5,000 individuals. This disease is characterized by small arteriovenous malformations (AVMs) in mucocutaneous areas (telangiectases) and larger visceral AVMs in the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9-10/ENG/ALK1/SMAD4 signaling pathway. […] Specifically, mutations in ENG (chromosomal locus 9q34.11, encoding the coreceptor endoglin) and ACVRL1 (chromosomal locus 12q13.13, encoding the type I receptor ALK1) are nearly equally responsible for the majority of HHT cases and give rise to the two major forms of the disease, HHT1 (OMIM 187300) and HHT2 (OMIM 600376), respectively. […] Together, mutations in ENG, ACVRL1, and SMAD4 are responsible for more than 90% of HHT cases, leaving a minority of clinically diagnosed individuals with an unknown genetic basis.

• #4 Hereditary hemorrhagic telangiectasia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hht/symptoms-causes/syc-20351135

  Hereditary hemorrhagic telangiectasia (tuh-lan-jee-uk-TAY-zhuh) is a condition that’s passed through families, called inherited. It causes atypical links between arteries and veins called arteriovenous malformations (AVMs). […] HHT is a condition of gene changes, called genetic, that you get from your parents. It is an autosomal dominant disorder. That means if one of your parents has HHT, you have a 50% chance of getting it. If you have HHT, each of your children has a 50% chance of getting it from you.

• #5 Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis | Genetics in Medicine

  https://www.nature.com/articles/gim9201198

  Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. […] Mutations in at least five genes are thought to result in hereditary hemorrhagic telangiectasia, but mutations in two genes (ENG and ACVRL1/ALK1) cause approximately 85% of cases. […] HHT is caused by a disturbance in the TGF signaling pathway. TGF signaling is important in the regulation of many cellular processes such as proliferation, differentiation, adhesion, and migration. […] Current data suggest that most disease-causing mutations in ACVRL1 or ENG result in haploinsufficiency. […] Mutations in HHT genes lead to perturbation of vascular remodeling and the maintenance of vessel wall integrity.

• #6 Hereditary hemorrhagic telangiectasia: An overview of diagnosis and management in the molecular era for clinicians | Genetics in Medicine

  https://www.nature.com/articles/gim200439

  HHT is an autosomal-dominant disorder presently linked to two loci. Mutations of the ENG, localized to the long arm of chromosome 9 (9q33-q34.1), cause HHT1 (OMIM: 187300), whereas HHT2 (OMIM: 600376) is caused by mutations of the gene encoding activin A receptor, type II-like kinase 1 (ACVRL1; also called activin receptor-like kinase 1, ALK1), localized on the long arm of chromosome 12 (12q11-q14). ENG and ALK1 encode receptor proteins, which are members of the transforming growth factor- (TGF) superfamily. Thus, HHT is caused by a disturbance in the TGF signaling pathway. TGF signaling is important in the regulation of many cellular processes such as proliferation, differentiation, adhesion, and migration. However, the exact mechanism of how a disturbance of this pathway leads to HHT remains unclear.

• #7

  https://haematologica.org/article/view/8582

  Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that causes abnormal blood vessel formation. […] Genetic mutations that have been identified include ENG, ACVRL1/ALK1, and MADH4/SMAD4, among others. […] Patients with HHT have been found to have abnormal plasma concentrations of transforming growth factor-beta (TGF-) and vascular endothelial growth factor (VEGF) secondary to mutations in ENG, ACVRL1 and MADH4. […] All three identified causative genes are involved in cell signaling via the TGF-/BMP signaling pathway, which has roles in cell growth, apoptosis, smooth muscle cell differentiation, and vascular remodeling and maintenance. […] In patients with HHT, mutations in endoglin, ALK1, or one of several other proteins in this pathway alter the normal endothelial response.

• #8 Future treatments for hereditary hemorrhagic telangiectasia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1281-4

  HHT is an autosomal dominant genetic disease that commonly results from monoallelic mutations in either ENG (HHT1, OMIM #187300) or ACVRL1 (HHT2, OMIM #600376) genes. ACVRL1 encodes the BMP (Bone Morphogenetic Protein) receptor ALK1 (activin receptor-like kinase 1) whose expression is grossly restricted to the vascular and lymphatic endothelia. Endoglin (encoded by ENG) is also an endothelial-specific receptor for BMPs which is devoid of intracellular kinase activity and acts as a co-receptor in complex with ALK1. Mutations of either one of these two genes are observed in 90% of the genetically screened patients. […] It is exciting to observe that the products of these 4 mutated genes all belong to the same signaling pathway. Homodimeric BMP9 and BMP10, as well as the recently characterized BMP9-BMP10 heterodimer, are high-affinity ligands of a receptor complex comprising ALK1, endoglin and a BMP type II receptor (BMPRII or ACTRIIA or ACTRIIB). Under activation by BMP9/10, this receptor complex phosphorylates the transcription factors Smad1, Smad5 or Smad9. Dimers of phospho-Smad1, phospho-Smad5 or phospho-Smad9 associate in a trimeric complex with Smad4 and translocate into the endothelial cell nucleus where they bind to BMP-responsive elements on the promoters of target genes and either enhance or repress their expression. HHT is thus now considered as a disease of the BMP9/10 pathway rather than a disease of the TGF pathway, as initially thought.

• #9

  https://link.springer.com/article/10.1007/s10792-021-02197-y

  Hereditary haemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber syndrome is a rare autosomal dominant disease, characterised by systemic angiodysplasia. Dysfunction of the signalling pathway of transforming growth factor is the main cause of HHT principally owing to mutations of the genes encoding for endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1). […] The genes implicated in the disease are critical for blood vessel development and response to TGF- signalling. Mutations causing HHT type I and II are commonly of Endoglin (ENG) on chromosome 9q33-34, and Activin A Receptor Like Type 1 (ACVRL-1) receptor on chromosome 12q13, respectively. Both genes code a membrane glycoprotein that is expressed in endothelial tissue cells and make up the surface receptor for TGF- that mediates vascular remodelling by affecting extracellular matrix production. ENG, ACVRL 1, and TGF- function are essential for angiogenesis. […] A new locus for HHT (HHT type III) has been mapped to chromosome 5 and a fourth locus to chromosome 7.

• #10 Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management

  https://www.mdpi.com/2077-0383/11/17/5245

  The relationship between the endothelium and affected genes in HHT is based on the positive regulation of angiogenesis by ENG and ACVRL1, a process in which the pathways of endothelial cell migration and proliferation are central. […] All affected genes encode proteins that participate in the transforming growth factor β (TGF-β) signaling pathway. […] The TGF-β family is a large and continuously expanding group of regulatory polypeptides. […] BMP 9 and 10 are the main ligands of the TGF-β family involved in this HHT pathway. […] They exert their action through a heteromeric serine/threonine type I (RI) and type II (RII) transmembrane receptor and then through the Smad cascades. […] Endoglin plays a role as auxiliary receptor for dimerization and enhanced activation of ALK-1 and RII receptors.

• #11 Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management

  https://www.mdpi.com/2077-0383/11/17/5245

  The Smad family complexes translocate to the nucleus and contribute to the transcription of genes involved in matrix development or migration of the endothelium. […] ALK1 and ALK5 generate different signals and can play opposite roles in angiogenesis. […] TGF-β/ALK1 induces endothelial cell migration and proliferation, while TGF-β/ALK5 inhibits these effects and promotes extracellular matrix deposition. […] Depending on the circulating levels of TGF-β family members, one pathway is going to predominate compared to the other. […] In a low TGF-β environment, ALK1/Smad1/5/8 route will enhance cell proliferation and migration (active phase), while in a high TGF-β environment, ALK5/Smad2/3 route will promote extracellular matrix deposition (quiescent phase).

• #12 Hereditary hemorrhagic telangiectasia: An overview of diagnosis and management in the molecular era for clinicians | Genetics in Medicine

  https://www.nature.com/articles/gim200439

  A fine balance between ALK1 and ALK5, both of which are TRI molecules, plays an important role in angiogenesis. Although TGF signaling is through ALK5 in many cell types, in ECs, both ALK1 and ALK5 are utilized. ALK1 is a positive regulator of angiogenesis, whereas ALK5 inhibits proliferation and migration of ECs. ENG regulates the ALK1/ALK5 balance by favoring ALK1 in ECs. Hence, mutations in either ENG or ALK1 cause similar findings. […] In summary, although dominant-negative mechanism cannot be ruled out for some ENG mutations, haploinsufficiency is considered to be the main mechanism leading to HHT.

• #13 Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management

  https://www.mdpi.com/2077-0383/11/17/5245

  Hereditary hemorrhagic telangiectasia (HHT) is an inherited disease related to an alteration in angiogenesis, manifesting as cutaneous telangiectasias and epistaxis. […] In recent years, there has been an advance in the understanding of the pathophysiology of the disease, which has allowed the use of new therapeutic strategies to improve the quality of life of patients. […] The haploinsufficiency model in HHT is the most accepted theory for the pathogenesis of disease development. […] It is explained by the fact that mutations in ENG and ACVRL1 genes generate altered proteins that fail to be expressed in the cell membranes of endothelial cells. […] This lack of protein expression results in impairment on routes via ENG or ACVRL1 that normally enhances endothelial migration and proliferation.

• #14

  https://www.jci.org/articles/view/176379

  The LOF nature of HHT causal mutations and the autosomal dominant inheritance of the disease led to the longstanding belief that HHT is caused by haploinsufficiency of the mutated gene product. […] However, the haploinsufficiency model does not explain why HHT vascular lesions develop focally in characteristic vascular beds despite the presence of the germline HHT causal mutation in all endothelial cells (ECs) of the body. […] This hypothesis implies that the germline mutation (first hit) predisposes the endothelium to vascular defects that strictly develop in the presence of additional, local factors (second hit) that could be either environmental or genetic. […] Several preclinical studies have demonstrated the role of proangiogenic and proinflammatory triggers in driving HHT pathogenesis. […] BMP9-10/ENG/ALK1/SMAD4 signaling maintains vascular homeostasis via attenuation of proangiogenic pathways and, in particular, the VEGF signaling pathway. […] The current working model suggests that BMP9-10/ENG/ALK1/SMAD4 signaling maintains vascular quiescence by repressing angiogenic pathways.

• #15 Hereditary Hemorrhagic Telangiectasia (HHT) | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/141559

  Hereditary hemorrhagic telangiectasia (HHT) is an inherited (autosomal dominant) disease that results in malformed blood vessels. The malformations typically manifest as mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). These vascular malformations are responsible for much of the clinical bleeding associated with this disease, ranging from mild epistaxis to life-threatening intracranial bleeds. […] HHT is an autosomal dominant disorder affecting blood vessels within multiple organ systems. The condition is suspected of haploinsufficiency, where 1 functional gene copy cannot produce the required protein to preserve function. In 97% of patients with a definite clinical HHT diagnosis, a causative mutation is identified in 1 of 3 genes described below. These mutations disrupt signaling by transforming growth factor-beta (TGF-B), essential for maintaining vascular integrity.

• #16 Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management

  https://www.mdpi.com/2077-0383/11/17/5245

  Importantly, animal models show that involvement of the endoglin and ALK1 pathways will also lead to a decrease in ALK5 pathway activity as a possible adaptation response to compensate the reduced expression of endoglin and ALK1. […] This would explain why there is an alteration in both the migration of endothelial cells and the subsequent formation of the cellular matrix in this pathology. […] Two other less recognized theories about the development of HHT are the dominant negativity theory and the double knockout hypothesis. […] The first searches to explain the development of the disease in patients with nonsense mutations in the ENG and ACVRL1 genes. […] On the other hand, somatic mutations in telangiectases of the skin have driven to propose a double hit hypotheses. […] This hypotheses could help to explain the increase in number of manifestation with the age of the patients.

• #17 Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: clinical aspects – Meier – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/18281/html

  HHT is inherited in an autosomal dominant pattern, affecting more than 1 in 10,000 people worldwide and results from mutations in genes that encode proteins critical to transforming growth factor beta (TGF-) signaling. […] Most cases involve mutations in two such genes, endoglin and ACVRL1. Pathogenic mutations in endoglin, which encodes a type III TGF- receptor, are associated with early HHT onset and a tendency for lung and brain AVMs. […] The mechanisms by which defects in TGF- signaling lead to the vascular malformations of HHT remain incompletely understood. […] Reduced expression of endoglin or ALK1 is probably not sufficient by itself to result in defective angiogenesis since most vascular beds develop normally in patients with HHT. […] Instead, a two-hit hypothesis has been proposed postulating that a trigger for abnormal blood vessel formation must exist on top of the underlying genetic defect.

• #18 Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions

  https://www.mdpi.com/2073-4425/12/2/174

  Although there is a growing consensus that HHT is caused by reduced BMP9/10 signalling in ECs, it is not yet clear why the vascular lesions are localised to specific organs and tissues. […] To summarise, in addition to genetic loss of ENG or ACVRL1, developmental angiogenesis, blood flow and local environmental triggers driving neovessel formation, such as hypoxia and inflammation, are critical players driving the formation of AVMs in HHT.

• #19

  https://haematologica.org/article/view/8582

  The haploinsufficiency of these proteins along with a second hit, such as tissue injury, infection or hypoxia, likely cause the focal vascular lesions of HHT1 and HHT2 as reduced levels of endoglin or ALK1 cannot maintain the balance needed for normal blood vessel formation. […] Vascular endothelial growth factor, an endothelial-specific factor for angiogenesis, is of major interest in diseases of vascular malformation and is elevated in HHT patients. […] Therefore, any mutation along the ALK1 pathway (BMP9, ACVRL1, ENG, MADH4) results in elevation of VEGF through reduced ALK1 pathway signaling. […] While this is a simplified discussion of complex vascular biology, it illustrates why mutations in ENG, ACVRL1/ALK1, MADH4/SMAD4, and BMP9/GDF2 result in the HHT phenotype.

• #20

  https://journals.lww.com/ajg/fulltext/2024/10001/s3661_the_perpetual_hemorrhage__managing_recurrent.3662.aspx

  Hereditary hemorrhagic Telangiectasia (HHT) is a genetic disorder that leads to arteriovenous malformations (AVMs) partly due to the lack of capillaries. […] The pathogenesis of HHT includes increased vascular endothelial growth factor (VEGF) expression causing aberrant angiogenesis. […] Endoscopic interventions may offer earlier detection of GI AVMs but may be futile in treating patients with HHT and recurrent GI bleeding as seen in our patient. […] One randomized control trial in 2023 found that in patients such as ours, using bevacizumab, an anti-VEGF antibody, may lead to patients requiring less transfusions.

• #21 Osler-Weber-Rendu Disease (Hereditary Hemorrhagic Telangiectasia): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2048472-overview

  OWRD (ie, HHT) is the first identified human disease caused by defects in a TGF- superfamily receptor. […] The clinical manifestations of OWRD are caused by the development of abnormal vasculature, including telangiectasias, AVMs, and aneurysms. […] Defects in the endothelial cell junctions, endothelial cell degeneration, and weakness of the perivascular connective tissue are thought to cause dilation of capillaries and postcapillary venules, which manifest as telangiectasias. […] Telangiectases and AVM bleeding tendency are attributed to localized vessel wall weakness, in part due to abnormal remodeling resulting from an imbalance in functions related to TGF-. […] Interactions with TGF- signaling result in disorganized cytoskeletal structure and poor vascular tubule formation. […] The genes most commonly implicated in HHT are the endoglin gene (ENG; HHT type 1) and the ALK-1 gene (ALK1; HHT type 2); other genes are less frequently involved.

• #22 Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: clinical aspects – Meier – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/18281/html

  In the proper genetic and environmental context, disordered angiogenesis leads to the vascular malformations observed in patients with HHT, including those in the lung. […] This process is thought to occur in a stepwise fashion starting with dilation of post-capillary venules followed by arteriolar dilation and then loss of the intervening capillary bed.

• #23

  https://omim.org/entry/187300

  A number sign (#) is used with this entry because hereditary hemorrhagic telangiectasia type 1 (HHT1) is caused by heterozygous mutation in the gene encoding endoglin (ENG; 131195) on chromosome 9q34. […] Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. […] The earliest clinically detectable lesion was a focal dilatation of postcapillary venules, which continued to enlarge and eventually connect with dilated arterioles through capillaries. […] As the vascular lesion increased in size, the capillary segments disappeared and a direct arteriovenous communication was formed. […] This sequence of events was associated with a perivascular mononuclear cell infiltrate in which most of the cells were lymphocytes and a minority are monocytes/macrophages by ultrastructural characteristics.

• #24 Hereditary Hemorrhagic Telangiectasia (HHT) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578186/

  The loss of vascular integrity, combined with constant pressure, results in telangiectasias (dilated microvessels) and large AVMs. […] Due to the vessel walls’ decreased elasticity and vascular lumen dilation, telangiectasias are fragile and more prone to hemorrhage. AVMs can form in the brain, lungs, GI tract, spine, or liver. […] Up to 10% of HHT patients have cerebral AVMs, 15 to 45% develop pulmonary AVMs, and 75% have hepatic AVMs. Rupture of these AVMs can result in severe complications, including internal hemorrhage, embolic or hemorrhagic stroke, seizures, migraines, or brain abscesses. […] There are phenotypic variations between HHT1 and HHT2. HHT1 patients develop epistaxis earlier in life and have pulmonary AVMs, while HHT2 patients are likelier to develop hepatic AVMs.

• #25 Neurovascular Manifestations of Hereditary Hemorrhagic Telangiectasia: A Consecutive Series of 376 Patients during 15 Years | American Journal of Neuroradiology

  https://www.ajnr.org/content/37/8/1479

  Our study of 376 patients with hereditary hemorrhagic telangiectasia demonstrated a high prevalence of brain arteriovenous malformations. Nidal brain arteriovenous malformations and capillary vascular malformations occurred in roughly equal numbers. Patients with brain arteriovenous malformations were more likely to be female and have a family history of hereditary hemorrhagic telangiectasia. The prevalence of brain arteriovenous malformation was 19.7% in endoglin (ENG) mutations and 12.5% in activin receptor-like kinase (ACVRL1) mutations. […] Our study of 376 consecutive patients with a diagnosis of definite HHT found the prevalence of BAVMs to be 12.8%, with a relatively even split between capillary vascular malformations and nidus-type BAVMs. More than 80% of BAVMs were supratentorial. Only 3% had a nidus size of 3 cm, and 20% had deep venous drainage. Approximately 10% of patients with BAVMs presented with rupture. Variables associated with the presence of a BAVM included female sex and a positive family history of HHT. Similar to prior studies, we demonstrated a higher prevalence of both single and multiple BAVMs among patients with ENG mutations. These findings are important because they provide further insight into the prevalence, risk factors, and characteristics of cerebral AVMs in the HHT population.

• #26 Frequently Asked Questions about Hereditary Hemorrhagic Telangiectasia (HHT)

  https://www.upmc.com/services/hht/frequently-asked-questions

  HHT is a genetic disease. It happens when a person inherits a mutated gene from his or her parents. […] In HHT, an error in your genetic blueprints causes you to produce a single defective protein. That defective protein leads to the development of abnormal blood vessels. […] The lab will study the genes that cause HHT endoglin, ACVRL-1, or SMAD-4 for abnormalities (called mutations). […] There are some differences in HHT risks, depending on your specific mutation. […] People with SMAD-4 may develop multiple polyps in the GI tract (called juvenile polyposis).

• #27 Osler-Weber-Rendu Disease (Hereditary Hemorrhagic Telangiectasia): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2048472-overview

  Endoglin and ALK-1 are type III and type I TGF- receptors, and both are exclusively expressed on vascular endothelial cells. […] The binding of TGF- to the type II TGF- receptor on endothelial cells, which is accelerated in the presence of endoglin, results in the phosphorylation of the type I TGF- receptors ALK-5 and ALK-1. […] Histopathologic studies reveal large, irregular, thinly walled blood vessels, but the pathogenesis has not been fully established. […] One theory states that systemic nevus vascular damage may not be equally expressed in all individuals with HHT.

• #28 Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis | Genetics in Medicine

  https://www.nature.com/articles/gim9201198

  Analysis of mice carrying mutations in either ENG or ACVRL1 has provided insight into the molecular mechanisms through which they act. Mouse embryos lacking either ENG or ACVRL1 develop AVMs and other HHT features. […] Thus, ENG and ACVRL1 are necessary for recruitment of vSMC and the differentiation of vSMC, during the development of vascular system.

• #29 Hereditary hemorrhagic telangiectasia and pregnancy: potential adverse | IJWH

  https://www.dovepress.com/hereditary-hemorrhagic-telangiectasia-and-pregnancy-potential-adverse–peer-reviewed-fulltext-article-IJWH

  Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant condition with a prevalence of ~1 in 5,000 individuals. The pathophysiology of this condition centers on the lack of capillary beds between arterioles and venules, leading to direct contact between these vessels. This results in telangiectases on characteristic locations such as the face, fingers, mouth, and nasal mucosa. […] The pathophysiology of HHT centers on an inability to properly connect arterioles and venules, such that they come into direct contact without an intervening capillary bed. It is theorized that an inability to properly recruit smooth muscle cells during angiogenesis may be a contributing factor. This hypothesis is tenable since the known mutations implicated in HHT affect the TGF- signaling pathway associated with angiogenesis.

• #30 Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9457069/

  Importantly, animal models show that involvement of the endoglin and ALK1 pathways will also lead to a decrease in ALK5 pathway activity as a possible adaptation response to compensate the reduced expression of endoglin and ALK1. […] Endoglin could help as an adhesion molecule for leukocyte infiltration. […] It has been proposed that during inflammation, endoglin is excised and its soluble fraction (sol-eng) could promote adhesion and chemotaxis for mononuclear cells (MNC). […] The alteration in signaling via endoglin and ALK1 in MNCs has been proposed as a justification for the alteration in the immune response present in these patients, such as a higher incidence of infections or leukopenia. […] Another approach currently being developed attempts to identify alterations in the coagulation and fibrinolysis cascades in HHT. […] It has been identified that patients with HHT present elevated levels of factor VIII and von Willebrand factor, indicating that these patients could present a higher risk of venous thrombosis than the general population.

• #31 Pathophysiology of Hereditary Hemorrhagic Telangiectasia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/28071

  This lack of protein expression results in impairment on routes via ENG or ACVRL1 that normally enhances endothelial migration and proliferation. […] Importantly, animal models show that involvement of the endoglin and ALK1 pathways will also lead to a decrease in ALK5 pathway activity as a possible adaptation response to compensate the reduced expression of endoglin and ALK1. […] This would explain why there is an alteration in both the migration of endothelial cells and the subsequent formation of the cellular matrix in this pathology. […] Endoglin could help as an adhesion molecule for leukocyte infiltration. […] In HHT, leukocyte infiltration mediated by the expression of adhesion molecules and chemokines synthesized by the endothelium could be impaired, affecting vascular repair and remodeling. […] Another approach currently being developed attempts to identify alterations in the coagulation and fibrinolysis cascades in HHT.

• #32 Hereditary Hemorrhagic Telangiectasia (HHT) | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/141559

  Pathogenesis of HHT is primarily due to the gene mutations (endoglin, ACVRL1, and SMAD4) that affect the endothelial cell receptors of the TGF-B superfamily. A mutation in these receptors prevents downstream signaling and disrupts angiogenesis, promoting a disorganized cytoskeleton and dysfunctional remodeling of the vascular endothelium. As a result, these vessels lose elasticity and remain chronically dilated. The loss of vascular integrity, combined with constant pressure, results in telangiectasias (dilated microvessels) and large AVMs. […] Due to the vessel walls’ decreased elasticity and vascular lumen dilation, telangiectasias are fragile and more prone to hemorrhage. AVMs can form in the brain, lungs, GI tract, spine, or liver. Up to 10% of HHT patients have cerebral AVMs, 15 to 45% develop pulmonary AVMs, and 75% have hepatic AVMs. Rupture of these AVMs can result in severe complications, including internal hemorrhage, embolic or hemorrhagic stroke, seizures, migraines, or brain abscesses.

• #33 Future treatments for hereditary hemorrhagic telangiectasia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1281-4

  Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000-8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations of ACVRL1 or ENG genes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the gene SMAD4 which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, no mechanism-based targeted therapy is available so far. In this review, we will focus on the development of new drugs aiming at correcting the altered signaling pathways in HHT patients. These include drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway as well as repositioned drugs identified by high throughput screening strategies.

• #34 Future treatments for hereditary hemorrhagic telangiectasia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1281-4

  Altogether, BMP9 and BMP10 maintain vascular quiescence by shutting down the pro-angiogenic VEGF and ANGPT2 signaling pathways. […] Although current treatments succeed pretty well at reducing recurrent epistaxis, there is still a need for magic bullets allowing to revert telangiectasias and AVMs into a normal vasculature and to definitely cure the disease. Two distinct drug repositioning strategies have been developed recently to achieve this goal. One is to reposition anti-angiogenic drugs used in cancer therapy (anti-VEGF antibody, tyrosine-kinase inhibitors) for counter-balancing the pro-angiogenic process activated in HHT. The other is to blindly screen drug libraries using an HHT mechanism-based cellular assay. […] Since the discovery some 25 years ago that ENG or ACVRL1 gene mutations cause HHT, significant progress has been made in the comprehension of the biological mechanisms of this pathology. It is puzzling however, that no etiological therapeutic treatment targeting the mutated components of the BMP9/10-ALK1-Smad1/5/9 signaling pathway has been developed so far. This review focuses on the possible repositioning of existing drugs that either correct the angiogenic defects of HHT patients (Bevacizumab, tyrosine kinase inhibitors, PI3 Kinase inhibitors) or reactivate the altered BMP9/10 signaling pathway (Tacrolimus, Sirolimus). It is now reasonably predictable that these mechanism-driven drugs will soon enter clinical assays and enlarge the therapeutic arsenal available for the treatment of HHT patients.

• #35 Hereditary Hemorrhagic Telangiectasia (HHT) – with Dr. Raj Kasthuri | Department of Medicine

  https://www.med.unc.edu/medicine/news/chairs-corner/podcast/hht-kasthuri/

  There are three genes that are known to be involved in HHT, and all of them are involved in various aspects of the same signaling pathway involving the lining of the blood vessel, the endothelium. […] Eighty percent of HHT, we believe is explained by endoglin mutations, or ALK-1 mutations. […] The latest advance in HHT is the use of anti-angiogenic approaches to treat HHT, where we can use medications that are now approved primarily in the world of oncology to treat cancer as an adjunct to chemotherapy, and these drugs are targeted at the development of blood vessels, where they prevent the development of new blood vessels, which is something we can then exploit in a disorder where the problem is primarily development of abnormal new blood vessels.

• #36 MicroRNAs as promising biomarkers and therapeutic tools in hereditary hemorrhagic telangiectasia – Research Outreach

  https://researchoutreach.org/articles/micrornas-promising-biomarkers-therapeutic-tools-hereditary-hemorrhagic-telangiectasia/

  Given the importance of TGF- signalling in the pathogenesis of HHT, it seems likely that the dysregulation of angiomiRs plays a role in HHT. […] Although further research is required, this may be an important pathogenic mechanism involved in abnormal blood vessel formation in HHT and could provide a unique miR therapeutic target. […] With further research, miRs may prove to have both diagnostic and therapeutic applications for those with HHT.

• #37 Hereditary Hemorrhagic Telangiectasia (HHT) > Fact Sheets > Yale Medicine

  https://www.yalemedicine.org/conditions/hht

  The location and size of the AVM determines what course of treatment is recommended. […] While there is no cure for HHT, Dr. Pollak says, together at Yale Medicine, we are working to prevent needless tragedies by diagnosing the disorder early and providing excellent treatment to patients and their families with continued monitoring.

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