An endothelial activin A-bone morphogenetic protein receptor type 2 link is overdriven in pulmonary hypertension.

Abstract

Pulmonary arterial hypertension is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular endothelial cells, we identify inhibin-β-A as an angiocrine factor produced by pulmonary capillaries. We find that excess production of inhibin-β-A by endothelial cells impairs the endothelial function in an autocrine manner by functioning as activin-A. Mechanistically, activin-A induces bone morphogenetic protein receptor type 2 internalization and targeting to lysosomes for degradation, resulting in the signal deficiency in endothelial cells. Of note, endothelial cells isolated from the lung of patients with idiopathic pulmonary arterial hypertension show higher inhibin-β-A expression and produce more activin-A compared to endothelial cells isolated from the lung of normal control subjects. When endothelial activin-A-bone morphogenetic protein receptor type 2 link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of inhibin-β-A in endothelial cells prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial activin-A-bone morphogenetic protein receptor type 2 link in the progression of pulmonary hypertension, and thus endothelial inhibin-β-A/activin-A might be a potential pharmacotherapeutic target for the treatment of pulmonary arterial hypertension.

• Authors: Gusty R T Ryanto, Koji Ikeda, Kazuya Miyagawa, Ly Tu, Christophe Guignabert, Marc Humbert, Tomoyuki Fujiyama, Masashi Yanagisawa, Ken-Ichi Hirata, Noriaki Emoto
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 1720 (03 19 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33741934 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• activin A
• inhibin B
• inhibin beta A subunit
• Activins
• Inhibins
• Inhibin-beta Subunits
• BMPR2 protein, human
• Bone Morphogenetic Protein Receptors, Type II

Topics

• Activins (metabolism)
• Animals
• Apoptosis
• Bone Morphogenetic Protein Receptors, Type II (genetics, metabolism)
• Disease Models, Animal
• Endocytosis
• Endothelial Cells (metabolism)
• Gene Knockout Techniques
• Humans
• Hypertension, Pulmonary (metabolism, pathology)
• Hypoxia
• Inhibin-beta Subunits
• Inhibins
• Lung (pathology)
• Mice
• Mice, Inbred C57BL
• Pulmonary Arterial Hypertension
• Vascular Remodeling