transforming-growth-factor-beta and Intracranial-Arteriovenous-Malformations

Patients who harbor brain arteriovenous malformations are at risk for intracranial hemorrhage. These malformations are often seen in inherited vascular diseases such as hereditary hemorrhagic telangiectasia. However, malformations within the brain also sporadically occur without a hereditary-coding component. Here, we review recent insights into the pathophysiology of arteriovenous malformations, in particular, certain signaling pathways that might underlie endothelial cell pathology. To better interpret the origins, determinants and consequences of brain arteriovenous malformations, we present a clinical case to illustrate the phenotypic landscape of the disease. We also propose that brain arteriovenous malformations might share certain signaling dimensions with those of anorectal hemorrhoids. This working hypothesis provides casual anchors from which to understand vascular diseases characterized by arteriovenous lesions with a hemorrhagic- or bleeding-risk component. Anat Rec, 2017. © The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. Anat Rec, 300:1973-1980, 2017. © 2017 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Topics: Activin Receptors, Type II; Adult; Arteriovenous Fistula; Blood Pressure; Brain; Dietary Fiber; Endoglin; Endothelial Cells; Humans; Intracranial Arteriovenous Malformations; Magnetic Resonance Angiography; Male; Mutation; Signal Transduction; Telangiectasia, Hereditary Hemorrhagic; Tomography, X-Ray Computed; Transforming Growth Factor beta

Hereditary haemorrhagic telangiectasia is a rare systemic autosomal dominantly inherited disorder of the fibrovascular tissue with a wide variety of clinical manifestations. Diagnosis is based on the clinical Curaçao criteria or molecular genetic testing. Dilated vessels can develop into telangiectases or larger vascular malformations in various organs, calling for an interdisciplinary approach. Epistaxis and gastrointestinal bleeding can result from these vascular defects. Various conservative and interventional treatments have been described for these conditions. However, no optimal therapy exists. Treatment can become especially difficult due to progressive anaemia or when anticoagulant or anti-thrombotic therapy becomes necessary. Screening for pulmonary arteriovenous malformations (PAVM) should be performed in all confirmed and suspected patients. Treatment by percutaneous transcatheter embolotherapy and antibiotic prophylaxis is normally effective for PAVM. Cerebral or hepatic vascular malformations and rare manifestations need to be evaluated on a case-by-case basis to determine the best course of action for treatment.

Topics: Anemia, Iron-Deficiency; Antibiotic Prophylaxis; Anticoagulants; Arteriovenous Malformations; Disease Management; Embolization, Therapeutic; Epistaxis; Fibrinolytic Agents; Gastrointestinal Hemorrhage; Hemostatics; Humans; Hypertension, Pulmonary; Intracranial Arteriovenous Malformations; Liver; Lung; Neovascularization, Pathologic; Signal Transduction; Telangiectasia, Hereditary Hemorrhagic; Thrombophilia; Transforming Growth Factor beta

Brain arteriovenous malformations (BAVMs) are thought to be sporadic developmental vascular lesions, but familial occurrence has been described. We compared the characteristics of patients with familial BAVMs with those of patients with sporadic BAVMs.. We systematically reviewed the literature on patients with familial BAVMs. Three families that were found in our centre were added. Age, sex distribution and clinical presentation of the identified patients were compared with those in population based series of patients with sporadic BAVMs. Furthermore, we calculated the difference in mean age at diagnosis of parents and children to study possible anticipation.. We identified 53 patients in 25 families with BAVMs. Mean age at diagnosis of patients with familial BAVMs was 27 years (range 9 months to 58 years), which was younger than in the reference population (difference between means 8 years, 95% CI 3 to 13 years). Patients with familial BAVMs did not differ from the reference populations with respect to sex or mode of presentation. In families with BAVMs in successive generations, the age of the child at diagnosis was younger than the age of the parent (difference between means 22 years, 95% CI 13 to 30 years), which suggests clinical anticipation.. Few patients with familial BAVMs have been described. These patients were diagnosed at a younger age than sporadic BAVMs whereas their mode of presentation was similar. Although there are indications of anticipation, it remains as yet unclear whether the described families represent accidental aggregation or indicate true familial occurrence of BAVMs.

Topics: Adolescent; Adult; Anticipation, Genetic; Child; Child, Preschool; Female; Humans; Infant; Intracranial Arteriovenous Malformations; Male; Middle Aged; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

In unruptured brain arteriovenous malformations (bAVMs), microhemorrhage portends a higher risk of future rupture and may represent a transitional state along the continuum of destabilization. Exploration of the molecular and cellular mechanisms of microhemorrhage will provide a possible target for medical treatment to prevent bAVM bleeding.. We performed RNA sequencing analysis on 34 unruptured bAVM surgical samples. Functional pathway analysis was performed to identify potential signals associated with the microhemorrhagic phenotype. Candidate gene was then investigated in bAVM specimens by immunohistochemical staining. Several functional assays were used to investigate the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells. Then, Masson trichrome staining and immunofluorescence staining were used to evaluate the phenotypic and molecular changes in bAVM tissue.. Via RNA sequencing, we identified differential gene expression between 18 microhemorrhagic bAVMs and 16 nonmicrohemorrhagic bAVMs. TGFβ (transforming growth factor-beta)/BMP (bone morphogenetic protein) signaling was associated with the bAVM microhemorrhage group when SMAD6 (SMAD family member 6) was downregulated. Immunohistochemical staining showed that the vascular endothelium of microhemorrhagic bAVMs exhibited decreased SMAD6 expression. Functional assays revealed that SMAD6 downregulation promoted the formation of endothelial cell tubes with deficient cell-cell junctions and facilitated the acquisition of mesenchymal behavior by endothelial cells. Masson trichrome and immunofluorescence staining demonstrated that mesenchymal phenotype of endothelial cells is promoted in microhemorrhagic bAVMs.. TGFβ/BMP signaling mediated by SMAD6 in vascular endothelial cells is associated with microhemorrhagic bAVMs, and mesenchymal behavior of endothelial cells induced by SMAD6 downregulation is related with bAVM microhemorrhage.

Topics: Adult; Arteriovenous Fistula; Cerebral Hemorrhage; Down-Regulation; Endothelial Cells; Female; Humans; Intracranial Arteriovenous Malformations; Male; Middle Aged; Signal Transduction; Smad6 Protein; Transforming Growth Factor beta

Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT. Common variants in candidate genes were reported as associated with sporadic brain AVM and/or ICH. We investigated whether these variants are associated with HHT organ VM or with ICH from brain VM in 752 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium.. We genotyped 11 candidate variants: four variants reported as associated with lung AVM in HHT (PTPN14 rs2936018, USH2A rs700024, ADAM17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH (APOE ε2, ANGPTL4 rs11672433, EPHB4 rs314308, IL6 rs1800795, IL1B rs1143627, ITGB8 rs10486391, TNFA rs361525). Association of genotype with any VM, lung AVM, liver VM, brain VM or brain VM ICH was evaluated by multivariate logistic regression adjusted for age, gender, and family clustering.. None of the 11 variants was significantly associated with any phenotype. There was a trend toward association of USH2A rs700024 with ICH (OR = 2.77, 95% CI = 1.13-6.80, p = .026).. We did not replicate previously reported associations with HHT lung AVM and variants in Tgfb modifier loci. We also did not find significant associations between variants reported in sporadic brain AVM and VM or ICH in HHT.

Topics: Adult; Aged; Brain; Central Nervous System Vascular Malformations; Female; Genetic Association Studies; Genotype; Humans; Intracranial Arteriovenous Malformations; Intracranial Hemorrhages; Liver; Lung; Male; Middle Aged; Mutation; Phenotype; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta; Vascular Malformations

Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM.. We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model.. Our study highlights the specific role of BMP/TGF-β and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.

Topics: Animals; Animals, Genetically Modified; Bone Morphogenetic Proteins; Brain; China; Cohort Studies; Disease Models, Animal; Exome Sequencing; Family; Female; Genetic Variation; Heterozygote; Humans; Intracranial Arteriovenous Malformations; Male; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Zebrafish

Brain arteriovenous malformations (BAVMs) are a rare but potentially devastating hemorrhagic disease. Transforming growth factor-beta signaling is required for proper vessel development, and defective transforming growth factor-beta superfamily signaling has been implicated in BAVM pathogenesis. We hypothesized that expression of the transforming growth factor-beta activating integrin, alphavbeta8, is reduced in BAVMs and that decreased beta8 expression leads to defective neoangiogenesis. We determined that beta8 protein expression in perivascular astrocytes was reduced in human BAVM lesional tissue compared with controls and that the angiogenic response to focal vascular endothelial growth factor stimulation in adult mouse brains with local Cre-mediated deletion of itgb8 and smad4 led to vascular dysplasia in newly formed blood vessels. In addition, common genetic variants in ITGB8 were associated with BAVM susceptibility, and ITGB8 genotypes associated with increased risk of BAVMs correlated with decreased beta8 immunostaining in BAVM tissue. These three lines of evidence from human studies and a mouse model suggest that reduced expression of integrin beta8 may be involved in the pathogenesis of sporadic BAVMs.

Topics: Animals; Arteriovenous Fistula; Brain; Case-Control Studies; Down-Regulation; Genetic Predisposition to Disease; Humans; Integrins; Intracranial Arteriovenous Malformations; Linkage Disequilibrium; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Physiologic; Polymorphism, Single Nucleotide; Transforming Growth Factor beta