scholarly journals Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia

2018 ◽  
Vol 19 (10) ◽  
pp. 3203 ◽  
Author(s):  
Veronique Vorselaars ◽  
Anna Hosman ◽  
Cornelis Westermann ◽  
Repke Snijder ◽  
Johannes Mager ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Clinical Signs ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Inherited Disease ◽  
Vascular Dysplasia ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-β) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.

Heritable pulmonary arterial hypertension

ESC CardioMed ◽  
2018 ◽  
pp. 2527-2528
Author(s):  
Charaka Hadinnapola ◽  
Nicholas Morrell
Keyword(s):  
Family History ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Gene Encoding ◽  
Causal Genes ◽  
History Of ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension (PAH) is diagnosed in patients presenting with PAH who have a family history of the disease or carry a mutation in a gene known to be associated with PAH. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the most common genetic defects seen in heritable PAH. Mutations in BMPR2 are found in 82% of patients with a family history of PAH and 17% of patients presenting with no family history of the disease. Other causal genes include members of the transforming growth factor beta pathway, including activing receptor-like kinase 1 (ACVRL1) and endoglin (ENG), as well as caveolin 1 (CAV1) and the potassium two-pore domain channel subfamily K member 3 (KCNK3).

scholarly journals TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients

2012 ◽  
Vol 71 (11) ◽  
pp. 1900-1903 ◽  
Author(s):  
Eugénie Koumakis ◽  
Julien Wipff ◽  
Philippe Dieudé ◽  
Barbara Ruiz ◽  
Matthieu Bouaziz ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Genes ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Tgfβ Receptor ◽  
Pulmonary Arterial

IntroductionSystemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) has emerged as a major mortality prognostic factor. Mutations of transforming growth factor beta (TGFβ) receptor genes strongly contribute to idiopathic and familial PAH.ObjectiveTo explore the genetic bases of SSc–PAH, we combined direct sequencing and genotyping of candidate genes encoding TGFβ receptor family members.Materials and methodsTGFβ receptor genes, BMPR2, ALK1, TGFR2 and ENG, were sequenced in 10 SSc–PAH patients, nine SSc and seven controls. In addition, 22 single-nucleotide polymorphisms (SNP) of these four candidate genes were tested for association in a first set of 824 French Caucasian SSc patients (including 54 SSc–PAH) and 939 controls. The replication set consisted of 1516 European SSc (including 219 SSc–PAH) and 3129 controls from the European League Against Rheumatism Scleroderma Trials and Research group network.ResultsNo mutation was identified by direct sequencing. However, two repertoried SNP, ENG rs35400405 and ALK1 rs2277382, were found in SSc–PAH patients only. The genotyping of 22 SNP including the latter showed that only rs2277382 was associated with SSc–PAH (p=0.0066, OR 2.13, 95% CI 1.24 to 3.65). Nevertheless, this was not replicated with the following result in combined analysis: p=0.123, OR 0.79, 95% CI 0.59 to 1.07.ConclusionsThis study demonstrates the lack of association between these TGFβ receptor gene polymorphisms and SSc–PAH using both sequencing and genotyping methods.

scholarly journals Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling

2020 ◽  
Vol 40 (11) ◽  
pp. 2605-2618
Author(s):  
Anne L. Theilmann ◽  
Lindsey G. Hawke ◽  
L. Rhiannon Hilton ◽  
Mara K.M. Whitford ◽  
Devon V. Cole ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
The Impact

Objective: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2 —the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with BMPR2 mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated BMPR2 silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional Bmpr2 knockout mice ( Bmpr2 EC −/− ). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFβ (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target ID1 in the context of BMPR2 loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice ( Bmpr2 EC+/+ ) but had no measurable effect on mice bearing a heterozygous endothelial Bmpr2 deletion ( Bmpr2 EC +/− ) and caused excessive angiogenesis in both vascular beds for Bmpr2 EC −/− mice. Conclusions: BMPR2 loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.

scholarly journals Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells

Angiogenesis ◽  
2020 ◽  
Vol 23 (4) ◽  
pp. 699-714
Author(s):  
Robert Szulcek ◽  
Gonzalo Sanchez-Duffhues ◽  
Nina Rol ◽  
Xiaoke Pan ◽  
Roula Tsonaka ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Phenotypic Change ◽  
Inflammatory Signaling ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial ◽  
Mesenchymal Transformation

Abstract Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown. Therefore, we treated primary PAH patient-derived and healthy pulmonary ECs with BMP9 and observed that stimulation induces transient transcriptional signaling associated with the process of endothelial-to-mesenchymal transition (EndMT). However, solely PAH pulmonary ECs showed signs of a mesenchymal trans-differentiation characterized by a loss of VE-cadherin, induction of transgelin (SM22α), and reorganization of the cytoskeleton. In the PAH cells, a prolonged EndMT signaling was found accompanied by sustained elevation of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling. Herein we identified interleukin-6 (IL6)-dependent signaling to be the central mediator required for the BMP9-induced phenotypic change in PAH pulmonary ECs. Furthermore, we were able to target the BMP9-induced EndMT process by an IL6 capturing antibody that normalized autocrine IL6 levels, prevented mesenchymal transformation, and maintained a functional EC phenotype in PAH pulmonary ECs. In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6.

First identification of Krüppel-like factor 2 mutation in heritable pulmonary arterial hypertension

2017 ◽  
Vol 131 (8) ◽  
pp. 689-698 ◽  
Author(s):  
Christina A. Eichstaedt ◽  
Jie Song ◽  
Rebecca Rodríguez Viales ◽  
Zixuan Pan ◽  
Nicola Benjamin ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Family Members ◽  
B Cell Lymphoma ◽  
Genetic Diagnostics ◽  
Heart Catheterization ◽  
Specific Gene ◽  
Inherited Disease ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension (HPAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene and/or genes of its signalling pathway in approximately 85% of patients. We clinically and genetically analysed an HPAH family without mutations in previously described pulmonary arterial hypertension (PAH) genes. Clinical assessment included electrocardiogram, lung function, blood gas analysis, chest X-ray, laboratory testing, echocardiography and right heart catheterization in case of suspected disease. Genetic diagnostics were performed using a PAH-specific gene panel including all known 12 PAH genes and 20 further candidate genes by next-generation sequencing (NGS). HPAH was invasively confirmed in two sisters and their father who died aged 32 years. No signs of HPAH were detected in five first-degree family members. Both sisters were lung transplanted and remained stable during a follow-up of >20 years. We detected a novel missense mutation in the Krüppel-like factor 2 (KLF2) likely leading to a disruption of gene function. The same KLF2 mutation has been described as a recurrent somatic mutation in B-cell lymphoma. Neither the healthy family members carried the mutation nor >120000 controls. These findings point to KLF2 as a new PAH gene. Further studies are needed to assess frequency and implication of KLF2 mutations in PAH patients.

scholarly journals The role of TGF-β or BMPR2 signaling pathway-related miRNA in pulmonary arterial hypertension and systemic sclerosis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Bei Xu ◽  
Guanhua Xu ◽  
Ye Yu ◽  
Jin Lin
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Protein Receptor ◽  
Growth Of Knowledge ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD), causing death in systemic sclerosis (SSc). The past decade has yielded many scientific insights into microRNA (miRNAs) in PAH and SSc. This growth of knowledge has well-illustrated the complexity of microRNA (miRNA)-based regulation of gene expression in PAH. However, few miRNA-related SSc-PAH were elucidated. This review firstly discusses the role of transforming growth factor-beta (TGF-β) signaling and bone morphogenetic protein receptor type II (BMPR2) in PAH and SSc. Secondly, the miRNAs relating to TGF-β and BMPR2 signaling pathways in PAH and SSc or merely PAH were subsequently summarized. Finally, future studies might develop early diagnostic biomarkers and target-oriented therapeutic strategies for SSc-PAH and PAH treatment.

scholarly journals Identification of novel rare sequence variation underlying heritable pulmonary arterial hypertension

2017 ◽  
Author(s):  
Stefan Gräf ◽  
Matthias Haimel ◽  
Marta Bleda ◽  
Charaka Hadinnapola ◽  
Laura Southgate ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor ◽  
Rare Variants ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Control ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

AbstractPulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

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