Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Hypertension. 2013 May;61(5):1044-52. doi: 10.1161/HYPERTENSIONAHA.111.199158. Epub 2013 Mar 11.
A deficiency in bone morphogenetic protein receptor type 2 (BMPR2) signaling is a central contributor in the pathogenesis of pulmonary arterial hypertension (PAH). We have recently shown that endothelial-specific Bmpr2 deletion by a novel L1Cre line resulted in pulmonary hypertension. SMAD1 is one of the canonical signal transducers of the BMPR2 pathway, and its reduced activity has been shown to be associated with PAH. To determine whether SMAD1 is an important downstream mediator of BMPR2 signaling in the pathogenesis of PAH, we analyzed pulmonary hypertension phenotypes in Smad1-conditional knockout mice by deleting the Smad1 gene either in endothelial cells or in smooth muscle cells using L1Cre or Tagln-Cre mouse lines, respectively. A significant number of the L1Cre(+);Smad1 (14/35) and Tagln-Cre(+);Smad1 (4/33) mutant mice showed elevated pulmonary pressure, right ventricular hypertrophy, and a thickening of pulmonary arterioles. A pulmonary endothelial cell line in which the Bmpr2 gene deletion can be induced by 4-hydroxy tamoxifen was established. SMAD1 phosphorylation in Bmpr2-deficient cells was markedly reduced by BMP4 but unaffected by BMP7. The sensitivity of SMAD2 phosphorylation by transforming growth factor-β1 was enhanced in the Bmpr2-deficient cells, and the inhibitory effect of transforming growth factor-β1-mediated SMAD2 phosphorylation by BMP4 was impaired in the Bmpr2-deficient cells. Furthermore, transcript levels of several known transforming growth factor-β downstream genes implicated in pulmonary hypertension were elevated in the Bmpr2-deficient cells. Taken together, these data suggest that SMAD1 is a critical mediator of BMPR2 signaling pertinent to PAH, and that an impaired balance between BMP4 and transforming growth factor-β1 may account for the pathogenesis of PAH.
骨形成蛋白受体 2 型（BMPR2）信号的缺陷是肺动脉高压（PAH）发病机制的主要原因。我们最近发现，通过一种新型 L1Cre 线对内皮细胞特异性 Bmpr2 的缺失导致了肺动脉高压。SMAD1 是 BMPR2 通路的经典信号转导物之一，其活性降低与 PAH 有关。为了确定 SMAD1 是否是 BMPR2 信号在 PAH 发病机制中的重要下游介质，我们分别使用 L1Cre 或 Tagln-Cre 小鼠线，通过在内皮细胞或平滑肌细胞中删除 Smad1 基因来分析 Smad1 条件性敲除小鼠的肺动脉高压表型。大量的 L1Cre(+)；Smad1(14/35)和 Tagln-Cre(+)；Smad1(4/33)突变小鼠表现出肺动脉高压、右心室肥厚和肺小动脉增厚。建立了一种可以通过 4-羟基他莫昔芬诱导 Bmpr2 基因缺失的肺内皮细胞系。BMP4 可显著降低 Bmpr2 缺陷细胞中的 SMAD1 磷酸化，但不受 BMP7 影响。BMP4 可增强转化生长因子-β1 对 SMAD2 磷酸化的敏感性，而 BMP4 可抑制转化生长因子-β1 介导的 SMAD2 磷酸化在 Bmpr2 缺陷细胞中受损。此外，几种已知的与肺动脉高压有关的转化生长因子-β下游基因的转录水平在 Bmpr2 缺陷细胞中升高。总之，这些数据表明 SMAD1 是与 PAH 相关的 BMPR2 信号的关键介质，BMP4 和转化生长因子-β1 之间的平衡失调可能是 PAH 的发病机制。
