Expression of Mutant BMPR-II in Pulmonary Endothelial Cells Promotes Apoptosis and a Release of Factors that Stimulate Proliferation of Pulmonary Arterial Smooth Muscle Cells

PVRI Member Authors: Paul Reynolds, Nicholas Morrell

Abstract

Mutations in the bone morphogenetic protein type II receptor gene (BMPR-II) are the major cause of heritable pulmonary arterial hypertension (PAH). Although both endothelial and smooth muscle cell BMPR-II dysfunction have been seen to contribute to pulmonary hypertension in vivo, little is known about the impact of BMPR-II mutation on the interaction between these two important cell types. We employed adenoviral vectors to overexpress wild type or mutant (kinase-deficient mutation, D485G) BMPR-II in human pulmonary arterial endothelial cells (PAECs). PAECs transfected with mutant BMPR-II demonstrated increased susceptibility to apoptosis. Conditioned media from PAECs transfected with mutant BMPR-II increased the proliferation of pulmonary arterial smooth muscle cells (PASMCs), when compared with conditioned media from PAECs transfected with wild-type BMPR-II. PAECs transfected with mutant BMPR-II released higher levels of TGF-β1 and FGF2 into the conditioned media than the wild-type BMPR-II-transfected cells. Conditioned media from PAECs expressing mutant BMPR-II also showed increased activation of luciferase activity in a TGF-β bioassay. The increased proliferation observed in PASMCs exposed to conditioned media from PAECs expressing mutant BMPR-II was inhibited by neutralizing the antibodies to TGF-β1, or small molecule inhibitors of ALK-5 (SD208) or FGFR1 (SU5402). We conclude that mutation in BMPR-II increases susceptibility to apoptosis of PAECs and leads to secretion of growth factors that stimulate the proliferation of PASMCs. These processes may contribute to the remodeling of pulmonary arteries observed in patients with familial or heritable PAH.

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Topics

Apoptosis
Epigenetics and Epigenomics
Pulmonary Vascular Remodeling

Authors

Xudong Yang, Lu Long, Paul N. Reynolds, Nicholas W. Morrell

Published in:

Pulmonary Circulation Vol 1: No 1 cover image

March 2011

Pulmonary Circulation Vol 1: No 1

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