Compton Leigh A, Potash Dru A, Mundell Nathan A, Barnett Joey V
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, USA.
Dev Dyn. 2006 Jan;235(1):82-93. doi: 10.1002/dvdy.20629.
During embryogenesis, epicardial cells undergo epithelial-mesenchymal transformation (EMT), invade the myocardium, and differentiate into components of the coronary vasculature, including smooth muscle cells. We tested the hypothesis that transforming growth factor-beta (TGFbeta) stimulates EMT and smooth muscle differentiation of epicardial cells. In epicardial explants, TGFbeta1 and TGFbeta2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon. Inhibition of activin receptor-like kinase (ALK) 5 blocks these effects, whereas constitutively active (ca) ALK5 increases cell invasion by 42%. Overexpression of Smad 3 did not mimic the effects of caALK5. Inhibition of p160 rho kinase or p38 MAP kinase prevented the loss of epithelial morphology in response to TGFbeta, whereas only inhibition of p160 rho kinase blocked TGFbeta-stimulated caldesmon expression. These data demonstrate that TGFbeta stimulates loss of epithelial character and smooth muscle differentiation in epicardial cells by means of a mechanism that requires ALK5 and p160 rho kinase.
在胚胎发生过程中，心外膜细胞经历上皮-间充质转化（EMT），侵入心肌，并分化为冠状血管系统的组成部分，包括平滑肌细胞。我们检验了转化生长因子-β（TGFβ）刺激心外膜细胞发生EMT和平滑肌分化的假说。在心外膜外植体中，TGFβ1和TGFβ2诱导上皮形态、细胞角蛋白以及膜相关紧密连接蛋白-1的丧失，并增加平滑肌标志物钙调蛋白和钙调素。激活素受体样激酶（ALK）5的抑制可阻断这些效应，而组成型激活（ca）ALK5使细胞侵袭增加42%。Smad 3的过表达并未模拟caALK5的效应。p160 Rho激酶或p38丝裂原活化蛋白激酶的抑制可防止TGFβ诱导的上皮形态丧失，而只有p160 Rho激酶的抑制可阻断TGFβ刺激的钙调素表达。这些数据表明，TGFβ通过一种需要ALK5和p160 Rho激酶的机制刺激心外膜细胞上皮特征的丧失和平滑肌分化。
