From the Department of Global Innovative Drug, Graduate School of Chung-Ang University, College of Pharmacy, Chung-Ang University, Seoul, Korea (Y.Y., J.-M.K., E.-K.J., S.S., R.-I.K., K.L.K., W.S.).
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (E.S.Y.).
Hypertension. 2020 Dec;76(6):1778-1786. doi: 10.1161/HYPERTENSIONAHA.120.15068. Epub 2020 Oct 26.
Loss of BMP (bone morphogenic protein) signaling induces a phenotype switch of pulmonary arterial smooth muscle cells (PASMCs), which is the pathological basis of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Here, we identified FGF12 (fibroblast growth factor 12) as a novel regulator of the BMP-induced phenotype change in PASMCs and elucidated its role in pulmonary vascular remodeling during PAH development. Using murine models of PAH and lung specimens of patients with PAH, we observed that FGF12 expression was significantly reduced in PASMCs. In human PASMCs, FGF12 expression was increased by canonical BMP signaling. knockdown blocked the antiproliferative and prodifferentiation effect of BMP on human PASMCs, suggesting that FGF12 is required for the BMP-mediated acquisition of the quiescent and differentiated PASMC phenotype. Mechanistically, FGF12 regulated the BMP-induced phenotype change by inducing MEF2a (myocyte enhancer factor 2a) phosphorylation via p38MAPK signaling, thereby modulating the expression of MEF2a target genes involved in cell proliferation and differentiation. Furthermore, we observed that TG (transgenic) mice with smooth muscle cell-specific overexpression were protected from chronic hypoxia-induced PAH development, pulmonary vascular remodeling, and right ventricular hypertrophy. Consistent with the in vitro data using human PASMCs, TG mice showed increased MEF2a phosphorylation and a substantial change in MEF2a target gene expression, compared with the WT (wild type) controls. Overall, our findings demonstrate a novel BMP/FGF12/MEF2a pathway regulating the PASMC phenotype switch and suggest FGF12 as a potential target for the development of therapeutics for ameliorating pulmonary vascular remodeling in PAH.
BMP（骨形态发生蛋白）信号的丧失会诱导肺动脉平滑肌细胞（PASMC）表型转换，这是肺动脉高压（PAH）中肺血管重构的病理基础。在这里，我们鉴定出 FGF12（成纤维细胞生长因子 12）是一种新的调节 BMP 诱导的 PASMC 表型变化的调节剂，并阐明了它在 PAH 发展过程中肺血管重构中的作用。使用 PAH 的小鼠模型和 PAH 患者的肺标本，我们观察到 FGF12 在 PASMC 中的表达显著降低。在人 PASMC 中，经典的 BMP 信号会增加 FGF12 的表达。FGF12 敲低阻断了 BMP 对人 PASMC 的抗增殖和促分化作用，表明 FGF12 是 BMP 介导获得静止和分化的 PASMC 表型所必需的。在机制上，FGF12 通过 p38MAPK 信号诱导 MEF2a（肌细胞增强因子 2a）磷酸化来调节 BMP 诱导的表型变化，从而调节涉及细胞增殖和分化的 MEF2a 靶基因的表达。此外，我们观察到平滑肌细胞特异性过表达 的 TG（转基因）小鼠对慢性低氧诱导的 PAH 发展、肺血管重构和右心室肥厚具有保护作用。与使用人 PASMC 的体外数据一致，与 WT（野生型）对照相比，TG 小鼠显示出 MEF2a 磷酸化增加和 MEF2a 靶基因表达的显著变化。总的来说，我们的研究结果表明，一种新的 BMP/FGF12/MEF2a 通路调节 PASMC 表型转换，并表明 FGF12 可能成为改善 PAH 中肺血管重构的治疗方法的潜在靶点。
