Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin (ENG) in HHT1 and activin receptor-like kinase 1 (ACVRL1; ALK1) in HHT2. Although both genes are involved in the transforming growth factor beta signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 (Alk1lacZ) by replacing its exons, including the one that encodes the transmembrane domain, with the beta-galactosidase gene. Using Alk1lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis. We also show that hemodynamic changes, which require vascular remodeling, may regulate Alk1 expression. Our studies suggest the role of Alk1 signaling in arterialization and remodeling of arteries. Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling.
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PMID:Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. 1297 Jan 15

Activin receptor-like kinase 1 (Acvrl1; Alk1) is a type I receptor for transforming growth factor-beta (TGF-beta). ALK1 plays a pivotal role in vascular development and is involved in the development of hereditary hemorrhagic telangiectasia 2 (HHT2), a dominantly inherited vascular disorder, and pulmonary hypertension. We have previously shown that Alk1 is expressed predominantly in arterial endothelial cells (ECs). Despite recent discoveries of a number of artery-specific genes, the regulatory elements of these genes have not been characterized. To investigate the cis-acting elements essential for the artery-specific Alk1 expression, we have generated a series of transgenic constructs with various lengths and regions of Alk1 genomic fragments connected to a LacZ reporter gene, and analyzed the reporter gene expression in transgenic mice. We found that a 9.2-kb genomic fragment, which includes 2.7-kb promoter region and the entire intron 2, is sufficient to drive arterial endothelium-specific expression. The defined regulatory region, as well as the transgenic mouse lines, would be invaluable resources in studying the mechanisms underlying angiogenesis, arteriogenesis, and vascular disorders, such as HHT and pulmonary hypertension. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Isolation of a regulatory region of activin receptor-like kinase 1 gene sufficient for arterial endothelium-specific expression. 1505 37

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder caused by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. We performed molecular characterization in clinically affected probands of 31 HHT families and detected a total of 28 different mutations in the two genes, including four shared by more than one family. Twelve mutations were identified in the ENG gene, six of which were novel and comprised two nonsense mutations in exons 6 and 8, deletions in exons 5 and 11, and splice site mutations in exon 12 and intron 8. Eleven of sixteen mutations identified in the ALK1 gene were novel single base pair substitutions in exons 4, 7, 8, and 9. We also describe the first de novo ALK1 mutation that causes a previously unreported c.1133C>A substitution of a highly conserved residue (p.P378H). The proband and his two daughters, who also carried the familial mutation, all suffered from gastrointestinal (GI) bleeding. In addition, we report seven newly identified polymorphisms and summarize all known ones in both genes.
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PMID:Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. 1571 71

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder originated by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. The first large series HHT analysis in Spanish population has identified mutations in 17 unrelated families. Ten different mutations in ALK1 and six in ENG genes were found. Six unrelated families had a mutation in ENG gene, four representing new mutations, p.Y258fs, pV323fs, p.F279fs (c.834_837del CTTC), and p.F279fsdupC. Eleven unrelated families harboured mutations in ALK1; ten were new mutations identified as p.H328P, p.R145fs, p.G68C, p.A377T, p.H297R, p.M376T, p.C36Y, p.H328P, p.T82del and p.R47P. Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1), in agreement with data reported for other Mediterranean countries (France, Italy), but at variance with Northern Europe or North America. Endoglin expression in HHT1 or HHT2 activated monocytes and blood outgrowth endothelial cells (BOECs) from older patients was well below the theoretical 50% level expected from the HHT1 haploinsufficiency model, suggesting that the pathogenic endoglin haploinsufficiency leading to the HHT phenotype is age-dependent. Interestingly, ALK1 protein levels of HHT BOECs in some missense ALK1 mutants were similar to controls. In vitro expression of these ALK1 constructs suggests that, in addition to the haploinsufficiency model, certain ALK1 mutants may inhibit the function of the wild type allele.
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PMID:Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1. 1647 May 89

Activin receptor-like kinase 1 (ALK1) is an endothelial-specific type I receptor of the TGFbeta receptor family that is implicated in angiogenesis and in the pathogenesis of the vascular disease, hereditary hemorrhagic telangiectasia (HHT). In the absence of a specific ligand, ALK1 cellular functions have been mainly studied through the use of a constitutively active form of this receptor (ALK1ca) and are still debated. We previously reported that ALK1ca inhibits proliferation and migration of human endothelial cells suggesting that ALK1 plays an important role in the maturation phase of angiogenesis (Lamouille et al., 2002, Blood 100: 4495-4501). In the present work, we further analyzed the role of ALK1 in the migration of human dermal microvascular endothelial cell (HMVEC-d) and observed that silencing endogenous ALK1 expression with siRNAs accelerates endothelial cell migration in the wound assay. Further, we demonstrate that ALK1-induced inhibition of migration is Smad-independent. Using a panel of kinase inhibitors, we found that HMVEC-d wound closure was completely inhibited by a JNK inhibitor and to a lower degree by an ERK kinase inhibitor. Further, HMVEC-d wounding induced activation of both JNK and ERK, and these were inhibited by ALK1ca expression. Taken together, these results support a significant role for ALK1 as a negative regulator of endothelial cell migration and suggest the implication of JNK and ERK as mediators of this effect.
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PMID:Activin receptor-like kinase 1 inhibits human microvascular endothelial cell migration: potential roles for JNK and ERK. 1762 Mar 21

Arteriovenous malformations (AVMs) are direct connections between arteries and veins associated with loss of the intervening capillary bed. In the lungs, pulmonary AVMs can result in right to left shunts and severe cyanosis and dyspnoea. However, the cellular and molecular mechanisms underlying AVM formation are poorly understood. One important clue comes from the fact that pulmonary AVMs frequently occur in the familial disease hereditary haemorrhagic telangiectasia (HHT), which is associated with mutations in one of two receptors involved in transforming growth factor-beta family signalling, either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). To elucidate the potential link between ENG or ACVRL1 deficiency and AVM formation in HHT, we performed a comprehensive study of Acvrl1 and Eng expression in wild-type and Eng-deficient (Eng+/-) mouse lungs using a combination of immunohistochemistry and RT-PCR from laser-microdissected arteries, veins and capillaries. We found that Eng and Acvrl1 have distinct expression profiles in the pulmonary vasculature and are only co-expressed in the distal (pre-capillary) arteries, distal veins and capillaries, consistent with the tendency for pulmonary AVMs to form in the distal pulmonary vessels in HHT. Downstream pSmad1/5/8 activity was found in the distal arteries and was specifically reduced in Eng+/- mice, consistent with previous in vitro data showing that Eng promotes Acvrl1-mediated Smad1/5/8 phosphorylation. Eng was more widely expressed than Acvrl1 in the lungs, as Eng alone was found in pulmonary veins, potentially explaining the increased frequency of AVMs in HHT1 patients. Furthermore, the association of ACVRL1 mutations with a second vascular disease, familial pulmonary artery hypertension, underlines the importance of ACVRL1 expression in the distal arteries that are affected in this disorder.
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PMID:Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH. 1901 42

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor beta pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploinsufficiency of ENG and ALK1.
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PMID:Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells. 2013 64

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disease hallmarked by the development of arteriovenous malformations (AVMs). Germline mutations in two genes, endoglin (ENG) and activin receptor like kinase 1 (ACVRL1), have been implicated in this disease. This report describes molecular diagnosis in a consecutive series of 600 individuals with clinical features of HHT disease. Each coding exon and flanking intronic regions of ENG and ACVRL1 genes was sequenced. Exonic copy number was quantified in probands without a coding sequence mutation. Novel nonsynonymous variants were further analyzed to predict functional consequences. In addition, common single nucleotide polymorphisms genotypes and haplotypes for the two genes were compared between individuals with and without mutations. The highest mutation detection rate (87% [95% CI 80.2-91.5]) was observed in probands who met all four Curacao criteria (epistaxis, telangiectases, AVMs and family history). More than 30% of identified mutations were novel; however, only 6% were variants of unknown significance. Determining the significance of novel mutations as related to disease presents additional challenges. Detection of multiple alterations in the same proband also requires careful evaluation for disease association. In conclusion, the sensitivity of molecular diagnosis is highest in probands with a clinically confirmed diagnosis of HHT. However, a substantial fraction of probands in this group do not carry an identifiable mutation in the coding exons of these two genes. This suggests alternate mechanisms of gene inactivation or involvement of alternate loci, and it requires further investigation.
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PMID:Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. 2041 77

Activin receptor-like kinase 1 (ACVRL1; ALK1) is predominantly expressed in arterial endothelial cells and plays an important role in angiogenesis. ACVRL1 mutations cause hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder for which the underlying mechanism is poorly understood. We have found that expression of transmembrane protein 100 (Tmem100) is downregulated in the lung of Acvrl1-deficient mice; however, its function is unknown. To elucidate the role of Tmem100 in vivo, we generated a conditional knockout allele for Tmem100 in which exon3, containing the entire coding sequence, was flanked by loxP sequences. The targeted allele also possessed a lacZ reporter cassette in intron2 for visualization of Tmem100 expression. We found that Tmem100 was predominantly expressed in arterial endothelial cells of developing embryos. The conditional and reporter allele will be a useful resource to investigate the in vivo role of Tmem100, especially in angiogenesis.
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PMID:Generation of mice with a conditional and reporter allele for Tmem100. 2084 92

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by a unique pattern of telangiectasia and arteriovenous malformations (AVMs). Mutations in one of two genes (ENG and ACVRL1) cause approximately 85% of cases. Genetic testing impacts clinical management because genotype/phenotype correlations exist, and early preventive screening for internal AVMs is recommended in affected individuals prior to the age at which a diagnosis can typically be made based on clinical criteria. We report 383 consecutive cases in which sequencing and large deletion/duplication analysis were performed simultaneously for endoglin (ENG) and activin-like receptor kinase 1 (ACVRL1). We report the first case of mosaicism in an affected individual and 61 novel mutations. We discuss the potential benefits of a diagnostic testing approach for HHT whereby ENG and ACVRL1 are analyzed simultaneously by sequencing and a method which detects large deletion/duplications, rather than by a sequential or reflex testing protocol. We report a case in which a deletion would probably have been missed if large deletion/duplication analysis was performed only if a suspected pathogenic mutation was not first identified by sequencing.
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PMID:Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. 2115 52


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