RT Journal Article SR Electronic T1 Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1100 OP 1110 DO 10.1183/09031936.00183008 VO 34 IS 5 A1 L. Dewachter A1 S. Adnot A1 C. Guignabert A1 L. Tu A1 E. Marcos A1 E. Fadel A1 M. Humbert A1 P. Dartevelle A1 G. Simonneau A1 R. Naeije A1 S. Eddahibi YR 2009 UL http://erj.ersjournals.com/content/34/5/1100.abstract AB 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.