He Junfeng, Wang Kejin, Wang Biao, Cui Yan, Zhang Qian
Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China.
Gansu Provincial Center for Disease Control and Prevention, Lanzhou 730070, China.
Animals (Basel). 2024 Jul 15;14(14):2072. doi: 10.3390/ani14142072.
To survive in low-oxygen environments, yaks effectively avoid hypoxia-induced pulmonary arterial hypertension through vascular remodeling. The TGF-β/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-β/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 TGFβ/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-β1 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-β1 activated the TGF-β 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-β/BMP signaling pathway promotes the proliferation of yak PASMCs.
为了在低氧环境中生存，牦牛通过血管重塑有效避免缺氧诱导的肺动脉高压。转化生长因子-β/骨形态发生蛋白（TGF-β/BMP）信号通路在维持肺动脉平滑肌细胞（PASMCs）的稳态中起关键作用。然而，关于TGF-β/BMP信号通路促进牦牛PASMCs增殖的分子调控机制知之甚少。在本研究中，体外培养牦牛PASMCs，并构建缺氧模型以研究TGFβ/BMP信号对牦牛PASMCs增殖的影响。缺氧处理显著增加了牦牛PASMCs的增殖。随着缺氧时间的延长，TGF-β1的表达水平和Smad2/3的磷酸化水平显著上调。BMP信号通路被缺氧短暂激活，BMPR2表达和Smad1/5磷酸化增加，随着缺氧暴露时间延长，这些变化逐渐逆转。此外，外源性TGF-β1激活了TGF-β信号通路，增加了下游蛋白Smad2和Smad3的磷酸化水平，并显著增加了牦牛PASMCs的增殖和迁移率。最后，用头蛋白（BMP信号的抑制剂）处理显著降低了BMPR2蛋白表达水平和Smad1/5磷酸化水平，并增加了牦牛PASMCs的增殖和迁移率。总之，这些结果表明，在缺氧条件下，TGF-β/BMP信号通路的动态调控促进了牦牛PASMCs的增殖。
