Effect of the TGF-ß/BMP Signaling Pathway on the Proliferation of Yak Pulmonary Artery Smooth Muscle Cells under Hypoxic Conditions.

ABSTRACT

To survive in low-oxygen environments, yaks effectively avoid hypoxia-induced pulmonary arterial hypertension through vascular remodeling. The TGF-ß/BMP signaling pathway plays a key role in maintaining the homeostasis of pulmonary artery smooth muscle cells (PASMCs). However, little is known about the molecular regulatory mechanisms by which the TGF-ß/BMP signaling pathway contributes to the proliferation of yak PASMCs. In this study, yak PASMCs were cultured in vitro, and a hypoxia model was constructed to investigate the effect of TGFß/BMP signaling on yak PASMC proliferation. Hypoxia treatment increased the proliferation of yak PASMCs significantly. As the duration of hypoxia increased, the expression levels of TGF-ß1 and the phosphorylation levels of Smad2/3 were upregulated significantly. The BMP signaling pathway was transiently activated by hypoxia, with increases in BMPR2 expression and Smad1/5 phosphorylation, and these changes were gradually reversed with prolonged hypoxia exposure. In addition, exogenous TGF-ß1 activated the TGF-ß signaling pathway, increased the phosphorylation levels of the downstream proteins Smad2 and Smad3, and increased the proliferation and migration rates of yak PASMCs significantly. Finally, treatment with noggin (an inhibitor of BMP signaling) significantly reduced BMPR2 protein expression levels and Smad1/5 phosphorylation levels and increased yak PASMC proliferation and migration rates. In summary, these results revealed that under hypoxic conditions, the dynamic regulation of the TGF-ß/BMP signaling pathway promotes the proliferation of yak PASMCs.