Interaction between bone morphogenetic proteins and endothelin-1 in human pulmonary artery smooth muscle

Genetic mutations in bone morphogenetic protein receptor 2 (BMPR2) have been shown to occur in patients with familial and idiopathic pulmonary arterial hypertension (PAH). However the interactions between ligands for this receptor and other mediators implicated in heritable PAH have not been investigated. This study examines the regulation of endothelin-1 (ET-1), a potent vasoconstrictor and comitogen that is implicated in the pathogenesis of heritable PAH, by ligands for the BMPR2. Immunohistochemical studies showed that pulmonary artery segments removed from normotensive human lungs express BMPR2 and bone morphogenetic proteins 2, 4 and 7 (BMP2, BMP4 and BMP7). In the presence of BMP7 and BMP4 there was a significant inhibition of ET-1 release, induced by cytokines, from cultured pulmonary artery smooth muscle cells. Fresh ring segments of pulmonary artery were assessed for their response to ET-1 in the presence and absence of BMP2, BMP4 and BMP7. BMP7 inhibited contraction in response to ET-1 in a concentration-dependent manner. BMP2 and BMP4 had no significant effect on the response to ET-1. These results suggest that BMP7 has the ability to regulate the effects of endothelin-1 in the pulmonary circulation. Genetic mutations in BMPR2 may lead to a loss of these regulatory mechanisms and contribute to the pathogenesis of pulmonary hypertension.