An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis.

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment.

An emerging class of new therapeutics targeting TGF, Activin, and BMP ligands in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an often fatal condition, the primary pathology of which involves loss of pulmonary vascular perfusion due to progressive aberrant vessel remodeling. The reduced capacity of the pulmonary circulation places increasing strain on the right ventricle of the heart, leading to death by heart failure. Currently, licensed therapies are primarily vasodilators, which have increased the median post-diagnosis life expectancy from 2.

Approaches to treat pulmonary arterial hypertension by targeting BMPR2: from cell membrane to nucleus.

Pulmonary arterial hypertension (PAH) is estimated to affect between 10 and 50 people per million worldwide. The lack of cure and devastating nature of the disease means that treatment is crucial to arrest rapid clinical worsening. Current therapies are limited by their focus on inhibiting residual vasoconstriction rather than targeting key regulators of the cellular pathology.

4PBA Restores Signaling of a Cysteine-substituted Mutant BMPR2 Receptor Found in Patients with Pulmonary Arterial Hypertension.

Mutations in the gene encoding BMPR2 (bone morphogenetic protein type 2 receptor) are the major cause of heritable pulmonary arterial hypertension (PAH). Point mutations in the BMPR2 ligand-binding domain involving cysteine residues (such as C118W) are causative of PAH and predicted to cause protein misfolding. Using heterologous overexpression systems, we showed previously that these mutations lead to retention of BMPR2 in the endoplasmic reticulum but are partially rescued by chemical chaperones.

Familial pulmonary arterial hypertension by heterozygous loss of function.

Beyond the major gene , several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the gene was found in a large genetic association study.We prospectively analysed the gene by targeted panel sequencing in a series of 311 PAH patients referred to a clinical molecular laboratory for genetic diagnosis of PAH.