transforming-growth-factor-beta and Vascular-Malformations

Patients with connective tissue diseases (CTDs) are suspected to be at higher risk for cerebrovascular involvement, such as intracranial aneurysms, dissections and strokes, than the general population. Particularly, Marfan Syndrome (MFS) has been reported as associated with an increased risk of cerebrovascular alterations. Literature data report different prevalence of intracranial aneurysms in MFS, ranging from 4 % to 29 %, suggesting a role of genetic cause that involves the regulation of the TGF-β signaling. Ischemic and hemorrhagic strokes have been also reported in MFS, but with an estimated prevalence from 3 % to 4 %. However, the aetiology of both events appears to be reliable more to a cardiac source than to the primary connective tissue defect. Finally, the available literature suggests that MFS patients have a higher prevalence of arterial tortuosity of neck and head vessels and these findings may be related to an enhanced chance of dissection. Overall, despite of the lack of studies, we could affirm that it may exists an increased prevalence of some neurovascular findings in MFS patients. Nevertheless, further studies are required to determine the true prevalence of these features and investigate specific gene mutations involved in MFS.

Topics: Arteries; Hemorrhagic Stroke; Humans; Intracranial Aneurysm; Ischemic Stroke; Joint Instability; Marfan Syndrome; Prevalence; Signal Transduction; Skin Diseases, Genetic; Transforming Growth Factor beta; Vascular Malformations

Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-β/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-β/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-β/BMP receptor complex and the second to increased signaling sensitivity to TGF-β/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.

Topics: Animals; Blood Vessels; Bone Morphogenetic Proteins; Disease Models, Animal; Genetic Predisposition to Disease; Hemangioma, Cavernous, Central Nervous System; Humans; Mice, Transgenic; Mutation; Neovascularization, Physiologic; Phenotype; Risk Factors; Signal Transduction; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta; Vascular Malformations

Venous malformations (VMs) are the most frequent vascular malformations and are characterized by dilated and tortuous veins with a dysregulated vascular extracellular matrix. The purpose of the present study was to investigate the potential involvement of microRNA-21 (miR-21), a multifunctional microRNA tightly associated with extracellular matrix regulation, in the pathogenesis of VMs.. The expression of miR-21, collagen I, III, and IV, transforming growth factor-β (TGF-β), and Smad3 (mothers against decapentaplegic homolog 3) was evaluated in VMs and normal skin tissue using in situ hybridization, immunohistochemistry, Masson trichrome staining, and real-time polymerase chain reaction. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanisms.. miR-21 expression was markedly decreased in the VM specimens compared with normal skin, in parallel with downregulation of collagen I, III, and IV and the TGF-β/Smad3 pathway in VMs. Moreover, our data demonstrated that miR-21 positively regulated the expression of collagens in HUVECs and showed a positive association with the TGF-β/Smad3 pathway in the VM tissues. In addition, miR-21 was found to mediate TGF-β-induced upregulation of collagens in HUVECs. Our data have indicated that miR-21 and the TGF-β/Smad3 pathway could form a positive feedback loop to synergistically regulate endothelial collagen synthesis. In addition, TGF-β/Smad3/miR-21 feedback loop signaling was upregulated in bleomycin-treated HUVECs and VM specimens, which was accompanied by increased collagen deposition.. To the best of our knowledge, the present study has, for the first time, revealed downregulation of miR-21 in VMs, which might contribute to decreased collagen expression via the TGF-β/Smad3/miR-21 signaling feedback loop. These findings provide new information on the pathogenesis of VMs and might facilitate the development of new therapies for VMs.

Topics: Bleomycin; Case-Control Studies; Cells, Cultured; Collagen; Down-Regulation; Feedback, Physiological; Human Umbilical Vein Endothelial Cells; Humans; MicroRNAs; Phosphorylation; Signal Transduction; Skin; Smad3 Protein; Transforming Growth Factor beta; Vascular Malformations; Veins

Venous malformations (VM) are localized defects in vascular morphogenesis manifested by dilated venous channels with reduced perivascular cell coverage. As a vital enzyme for extracellular matrix (ECM) deposition, lysyl oxidase (LOX) plays important roles in vascular development and diseases. However, the expression and significance of LOX are unknown in VM. Herein, 22 VM specimens and eight samples of normal skin tissues were evaluated immunohistochemically for the expression of LOX, α-smooth muscle cell actin (α-SMA) and transforming growth factor-β (TGF-β). In vitro studies on human umbilical vein endothelial cells (HUVEC) were employed for determining potential mechanisms. Our results showed that LOX expression was significantly reduced in VM compared with normal skin tissues, in parallel with attenuated perivascular α-SMA

Topics: Adolescent; Adult; Aged; Aminopropionitrile; Bleomycin; Child; Child, Preschool; Down-Regulation; Endothelium, Vascular; Extracellular Matrix; Female; Human Umbilical Vein Endothelial Cells; Humans; Infant; Male; Middle Aged; Protein-Lysine 6-Oxidase; Recombinant Proteins; Sclerotherapy; Skin; Transforming Growth Factor beta; Vascular Malformations; Veins; Young Adult

We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.. We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.. Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.. Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

Topics: Adolescent; Adult; Aorta; Arteries; Biopsy; Child; Child, Preschool; Connective Tissue Growth Factor; Female; Glucose Transport Proteins, Facilitative; Hernia, Diaphragmatic; Humans; Infant; Joint Instability; Male; Mutation; Pedigree; Respiratory Distress Syndrome, Newborn; Skin; Skin Diseases, Genetic; Smad2 Protein; Transforming Growth Factor beta; Vascular Malformations

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

Cerebrovascular malformations (CVMs) affect approximately 3% of the population, risking hemorrhagic stroke, seizures, and neurological deficits. Recently Ras mutations have been identified in a majority of brain arterio-venous malformations. We generated an endothelial-specific, inducible HRAS

Topics: Activin Receptors, Type II; Animals; Brain; Cells, Cultured; Endothelial Cells; Female; Fluorescent Antibody Technique; Imidazoles; Immunohistochemistry; Male; Mice; Mice, Transgenic; Pericytes; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Quinoxalines; Receptor, Transforming Growth Factor-beta Type I; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Vascular Malformations

Venous malformations (VMs) are characterized by ectatic and tortuous venous channels with decreased perivascular cell coverage. Recent studies have discovered that miR-145 plays a critical role in amounts of vascular diseases through regulating the differentiation and phenotype of vascular smooth muscle cells (VSMCs). However, the potential roles of miR-145 in VMs remain unknown. In this study, 21 samples of VMs without treatment history, and 10 samples of healthy donor skin, were collected to evaluate the expression level of TGF-β, miR-145, and α-SMA by immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction (PCR). Subsequently, their correlations were analyzed using the Spearman rank correlation test. In vitro studies were performed using human umbilical vein endothelial cells (HUVECs). The results showed that miR-145 was significantly downregulated in VMs compared with normal skin tissues, accompanied by a synchronously decreased TGF-β expression level and perivascular α-SMA

Topics: Bleomycin; Down-Regulation; Human Umbilical Vein Endothelial Cells; Humans; MicroRNAs; Sclerotherapy; Skin; Transforming Growth Factor beta; Vascular Malformations; Veins

N629D KCNH2 is a human missense long-QT2 mutation. Previously, we reported that the N629D/N629D mutation embryos disrupted cardiac looping, right ventricle development, and ablated IKr activity at E9.5. The present study evaluates the role of KCNH2 in vasculogenesis.. N629D/N629D yolk sac vessels and aorta consist of sinusoids without normal arborization. Isolated E9.5 +/+ first branchial arches showed normal outgrowth of mouse ERG-positive/α-smooth muscle actin coimmunolocalized cells; however, outgrowth was grossly reduced in N629D/N629D. N629D/N629D aortas showed fewer α-smooth muscle actin positive cells that were not coimmunolocalized with mouse ERG cells. Transforming growth factor-β treatment of isolated N629D/N629D embryoid bodies partially rescued this phenotype. Cultured N629D/N629D embryos recapitulate the same cardiovascular phenotypes as seen in vivo. Transforming growth factor-β treatment significantly rescued these embryonic phenotypes. Both in vivo and in vitro, dofetilide treatment, over a narrow window of time, entirely recapitulated the N629D/N629D fetal phenotypes. Exogenous transforming growth factor-β treatment also rescued the dofetilide-induced phenotype toward normal.. Loss of function of KCNH2 mutations results in defects in cardiogenesis and vasculogenesis. Because many medications inadvertently block the KCNH2 potassium current, these novel findings seem to have clinical relevance.

Topics: Abnormalities, Drug-Induced; Animals; Cells, Cultured; Embryo Culture Techniques; Embryonic Stem Cells; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Fetal Death; Gene Expression Regulation, Developmental; Genotype; Heart Defects, Congenital; Humans; Mice, 129 Strain; Mice, Transgenic; Morphogenesis; Mutation, Missense; Neovascularization, Physiologic; Phenethylamines; Phenotype; Potassium Channel Blockers; Signal Transduction; Sulfonamides; Transforming Growth Factor beta; Vascular Malformations

Topics: Abnormalities, Drug-Induced; Animals; Embryonic Stem Cells; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Fetal Death; Heart Defects, Congenital; Humans; Mutation, Missense; Neovascularization, Physiologic; Phenethylamines; Potassium Channel Blockers; Sulfonamides; Transforming Growth Factor beta; Vascular Malformations

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder caused by loss-of-function mutations in SLC2A10, which encodes facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose and/or dehydroascorbic acid, have not been clearly elucidated. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGFβ signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGFβ signalling due to TGFBRI disorganization, the upregulation of TGFBRII and connective tissue growth factor, and the activation of the αvβ3 integrin transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 expression in patients' fibroblasts normalized redox homeostasis and PPARγ activity, rescued canonical TGFβ signalling and induced partial ECM re-organization. These data add new insights into the ATS dysregulated biological pathways and definition of the pathomechanisms involved in this disorder.

Topics: Arteries; Extracellular Matrix; Fibroblasts; Gene Expression Profiling; Glucose Transport Proteins, Facilitative; Homeostasis; Humans; Integrin alphaVbeta3; Joint Instability; Mutation; Oxidative Stress; Signal Transduction; Skin; Skin Diseases, Genetic; Transforming Growth Factor beta; Vascular Malformations

Previous studies have implicated vascular destabilization and changes in extracellular matrix (ECM) composition in venous malformations (VMs).. To evaluate the expression levels of the connective tissue growth factor (CCN) family of matricellular proteins in VMs and explore their association with vascular destabilization.. The expression levels of CCNs 1-6, transforming growth factor (TGF)-β, phosphorylated Tie2 and phosphorylated platelet-derived growth factor receptor β in normal human skin tissues and VMs were detected by immunohistochemistry. Correlation between tested proteins was explored using the Spearman rank correlation test, followed by clustering analysis. In vitro studies using human umbilical vein endothelial cells (HUVECs) were performed for mechanism investigation.. Expression of CCN2 was found to be strongly positive in fibroblast-like cells, endothelial cells and around blood vessels in normal human skin tissues, but it was significantly downregulated in VMs. Correlation analyses showed that expression levels of CCN2 and TGF-β in VMs were positively correlated. The immunoreactivity of CCN2 was also closely correlated with perivascular α-smooth muscle cell actin(+) cell coverage in VMs. Moreover, in vitro studies in HUVECs indicated that CCN2 might act as a downstream target of TGF-β, as demonstrated by the findings that treatment with exogenous TGF-β or exogenous CCN2 could significantly upregulate the expression level of CCN2, and increase the expression levels of ECM components. Upregulation of the TGF-β/CCN2 pathway was also detected in bleomycin-treated VM specimens.. This study unmasks the downregulation of the TGF-β/CCN2 pathway in VMs, and indicates its target potential for sclerotherapy.

Topics: Adolescent; Adult; Child; Child, Preschool; Connective Tissue Growth Factor; Down-Regulation; Female; Human Umbilical Vein Endothelial Cells; Humans; Infant; Male; Middle Aged; Sclerotherapy; Signal Transduction; Transforming Growth Factor beta; Vascular Malformations; Young Adult

Venous malformations (VMs) are among the most common slow-flow vascular malformations characterized by irregular venous channels, luminal thrombi, and phleboliths. To systematically manifest the disorganized vascular structures in sporadic VMs, we initially evaluated histopathological characteristics, perivascular cell coverage, adhesion molecules expression and vascular ultrastructures. Then, the expression of Tie2 and TGF-β in VMs was detected. Meanwhile, the in vitro studies were performed for mechanism investigation. Our data showed that the perivascular α-SMA(+) cell coverage and expression of adhesion molecules in VMs were significantly decreased compared with those in the normal skin tissues. We also found that the expression and phosphorylation levels of Tie2 were upregulated, whereas TGF-β was downregulated in VMs, and they were negatively correlated. Moreover, the in vitro results also revealed a possible balancing effect between Tie2 and TGF-β, as demonstrated by the findings that Ang-1 (agonist of Tie2) treatment significantly downregulated TGF-β expression, and treatment with recombinant TGF-β could also suppress Tie2 expression and phosphorylation. This study provided strong evidence supporting the disorganized vascular structures and dysregulation of related molecules in sporadic VMs, and demonstrated a possible balancing effect between Tie2 and TGF-β, which might help to develop novel therapeutics for vascular disorganization-related disorders.

Topics: Cell Adhesion Molecules; Cells, Cultured; Female; Humans; Male; Models, Cardiovascular; Receptor, TIE-2; Signal Transduction; Statistics as Topic; Transforming Growth Factor beta; Vascular Malformations; Veins

Topics: Connective Tissue Growth Factor; Female; Humans; Male; Transforming Growth Factor beta; Vascular Malformations

The expression of growth factors and proliferation of endotheliocytes in vascular malformations were studied by immunohistochemical methods. The detected specific features of growth factor expression in the endothelium of venous and arteriovenous malformations seem to reflect the differences in the pathogenesis of these formations. High proliferative activity of the endothelium in angiodysplasias of both types can underlie the disease relapsing.

Topics: Adult; Aged; Arteriovenous Malformations; Endothelial Cells; Endothelium, Vascular; Female; Fibroblast Growth Factors; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Malformations; Young Adult