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Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension

¹ INSERM U955, Institut Mondor de recherche biomédicale, Créteil, ² UPRES EA2705, Laboratoire de Chirurgie Expérimentale, Centre Chirurgical Marie Lannelongue, Université Paris-Sud 11, Le Plessis Robinson, ³ INSERM U764, UPRES EA2705, Service de Pneumologie, Centre National de Référence de l’Hypertension Artérielle Pulmonaire, Hôpital Antoine-Béclère, Assistance-Publique Hôpitaux de Paris, Université Paris-Sud 11, Clamart, France, and ⁴ Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium.

CORRESPONDENCE: L. Dewachter, Dept of Physiology, Faculty of Medicine, Free University of Brussels, 808 Lennik Road, 1070 Brussels, Belgium. E-mail: ldewacht{at}ulb.ac.be

Keywords: Bone morphogenetic protein receptor type 2, intracellular signal transduction, mutation, pulmonary hypertension, smooth muscle cells, vascular remodelling

Received: December 2, 2008
Accepted March 12, 2009

Mutations in the gene encoding bone morphogenetic protein (BMP) receptor type 2 (BMPR-2) have been reported in pulmonary arterial hypertension (PAH), but their functional relevance remains incompletely understood.

BMP receptor expression was evaluated in human lungs and in cultured pulmonary artery smooth muscle cells (PASMCs) isolated from 19 idiopathic PAH patients and nine heritable PAH patients with demonstrated BMPR-2 mutations. BMP4-treated PASMCs were assessed for Smad and p38 mitogen-activated protein kinase (MAPK) signalling associated with mitosis and apoptosis.

Lung tissue and PASMCs from heritable PAH patients presented with decreased BMPR-2 expression and variable increases in BMPR-1A and BMPR-1B expression, while a less important decreased BMPR-2 expression was observed in PASMCs from idiopathic PAH patients. Heritable PAH PASMCs showed no increased phosphorylation of Smad1/5/8 in the presence of BMP4, which actually activated the p38MAPK pathway. Individual responses varied from one mutation to another. PASMCs from PAH patients presented with an in vitro proliferative pattern, which could be inhibited by BMP4 in idiopathic PAH but not in heritable PAH. PASMCs from idiopathic PAH and more so from heritable PAH presented an inhibition of BMP4-induced apoptosis.

Most heterogeneous BMPR-2 mutations are associated with defective Smad signalling compensated for by an activation of p38MAPK signalling, accounting for PASMC proliferation and deficient apoptosis.