Crosstalk between endothelin-1 and BMPR2 signaling contributes to smooth muscle cell hyperplasia

Background: Increased endothelin-1 (ET-1) production and bone morphogenetic protein (BMP) receptor type 2 (BMPR2) signaling deficiency have been incriminated in the pathogenesis of pulmonary arterial hypertension (PAH). However, little is known about the crosstalk between these signaling pathways and its potential implication in pulmonary artery smooth muscle cell (PASMC) hyperplasia in PAH. Aims and objectives: We sought to evaluate the effects of ET-1 on BMPR2 signaling and the functional impact of this on PASMC proliferation. Methods: Gene expressions of BMPR2, BMP agonist (BMP4) and BMP antagonists (gremlin1 and PRDC) were evaluated in primary cultured PASMCs isolated from PAH patients (n=5) and controls (n=12) treated with increasing concentrations of ET-1 (0.1 - 1 µM). In control PASMCs pretreated with ET-1 (0.1 – 1 µM), the effects of BMP2 (10 ng/mL) on PASMC proliferation and on inhibitor of DNA binding protein 1 (Id1) expression were assessed respectively by MTT assay and RTQ-PCR. Results: In PASMCs isolated from PAH patients, BMPR2 and BMP4 expressions decreased, while expressions of gremlin1 and PRDC increased. In control PASMCs, ET-1 induced increased expressions of gremlin1 and PRDC, while BMPR2 and BMP4 expressions dose-dependently decreased reaching similar levels, as those observed in PAH PASMCs. BMP2-treated control PASMCs presented increased Id1 expression, while this was reduced by ET-1 pretreatment. In control PASMCs, BMP2 inhibited serum-induced proliferation. This anti-proliferative effect was attenuated by ET-1 pretreatment. Conclusion: Endothelium-derived ET-1 downregulates BMPR2 signaling in PASMCs. This might contribute to PASMC hyperplasia observed in PAH.