Endothelin-1 contributes to the downregulation of BMP/BMPR2 signaling induced by hypoxia

Background: Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases. Alterations in bone morphogenetic protein (BMP) and endothelin signaling have been described in hypoxic PH. We recently reported on endothelin-induced downregulation of BMP signaling in pulmonary artery smooth muscle cells (PA-SMCs), partly through increased expression of BMP antagonist gremlin1. Here, we aimed to study the alterations in BMP signaling in hypoxia. Methods: Lung expressions of BMP antagonists noggin and gremlin1 were evaluated in 4 patients with group3 PH, 6 with idiopathic pulmonary arterial hypertension (iPAH) and 6 controls. Control PA-SMCs were treated with the hypoxia-mimetic agent cobalt chloride (CoCl2; 100 µM), with or without pre-treatment with bosentan (1 µM). Gene expressions of preproendothelin-1 (PPET1), endothelin converting enzyme 1 (ECE1), BMP type 2 receptor (BMPR2), noggin, gremlin1 and inhibitor of DNA binding 1 (Id1) were evaluated by RTQ-PCR. Results: Lung tissue from group3 PH patients presented with increased expression of noggin, gremlin1 and 2, while a less important increase was observed in iPAH lungs. Treatment of PA-SMCs with CoCl2 increased PPET1 expression, while it did not alter ECE1 expression. CoCl2 decreased BMPR2 and Id1 expressions, while it increased noggin and gremlin1 expression. In PA-SMCs, bosentan pretreatment prevented the alteration of Id1 and gremlin1 expressions induced by CoCl2, while it did not alter noggin and BMPR2. Conclusion: Hypoxia induces the downregulation of the BMP signaling in control PA-SMCs, partly through the endothelin system. This may account for the increased expression of gremlin1 observed in hypoxic PH patients.