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

Gusty R. T. Ryanto, Koji Ikeda (), Kazuya Miyagawa, Ly Tu, Christophe Guignabert, Marc Humbert, Tomoyuki Fujiyama, Masashi Yanagisawa, Ken-ichi Hirata and Noriaki Emoto
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Gusty R. T. Ryanto: Kobe Pharmaceutical University
Koji Ikeda: Kobe Pharmaceutical University
Kazuya Miyagawa: Kobe Pharmaceutical University
Ly Tu: INSERM UMR_S 999
Christophe Guignabert: INSERM UMR_S 999
Marc Humbert: INSERM UMR_S 999
Tomoyuki Fujiyama: University of Tsukuba
Masashi Yanagisawa: University of Tsukuba
Ken-ichi Hirata: Kobe University Graduate School of Medicine
Noriaki Emoto: Kobe Pharmaceutical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21961-3

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