Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension

J Heart Lung Transplant. 2015 Mar;34(3):468-78. doi: 10.1016/j.healun.2014.09.011. Epub 2014 Sep 28.

Abstract

Background: Endothelin receptor antagonists improve pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAH. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAH.

Methods: Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA-SMCs from 6 PAH patients and 14 controls treated with endothelin-1. Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment.

Results: In PA-SMCs from PAH patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAH cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAH patients.

Conclusions: Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti-BMP gremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation.

Keywords: BMPR2; Pulmonary arterial hypertension; endothelin; gremlin; proliferation; pulmonary artery smooth muscle cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Bone Morphogenetic Protein Receptors, Type II / genetics*
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Humans
  • Hyperplasia
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / pathology
  • Male
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Mutation*
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology*
  • RNA / genetics*
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction

Substances

  • RNA
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II