FGF2 inhibits endothelial-mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling
FGF2 inhibits endothelial-mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling
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DOI：
10.1242/jcs.176248
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发表时间：
2016-02-01
影响因子：
4
通讯作者：
Krenning, Guido
中科院分区：
文献类型：
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作者：
Correia, Ana C. P.;Moonen, Jan-Renier A. J.;Krenning, Guido
内皮-间充质转化（EndMT）的特征是内皮细胞标志物和功能的丧失，并且与间充质标志物的从头表达相一致。EndMT由TGF β 1诱导并改变内皮microRNA表达。我们发现miR-20 a在EndMT过程中减少，并且miR-20 a的异位表达抑制EndMT诱导。TGF β 1诱导人脐静脉内皮细胞中的细胞肥大并消除VE-钙粘蛋白表达，降低内皮发芽能力并诱导间充质标志物SM 22 α（也称为TAGLN）的表达。我们将ALK 5（也称为TGFBR 1）、TGFBR 2和SARA（也称为ZFYVE 9）鉴定为直接miR-20 a靶标。miR-20 a模拟物的表达通过降低ALK 5、TGFBR 2和SARA消除了内皮对TGF β 1的反应性，并抑制EndMT，如通过维持VE-钙粘蛋白表达、细胞出芽能力和不存在SM 22 α表达所指示的。在TGF β 1刺激的内皮细胞中，FGF 2增加miR-20 a表达并抑制EndMT。总之，FGF 2通过miR-20 a调节ALK 5、TGFBR 2和SARA表达来控制内皮TGF β 1信号传导。FGF 2信号传导的丧失与TGF β 1刺激相结合降低了miR-20 a水平，并通过升高的受体复合物水平和Smad 2和Smad 3的激活增加了内皮对TGF β 1的反应性，这在EndMT中达到高潮。
Endothelial-to-mesenchymal transition (EndMT) is characterized by the loss of endothelial cell markers and functions, and coincides with de novo expression of mesenchymal markers. EndMT is induced by TGF beta 1 and changes endothelial microRNA expression. We found that miR-20a is decreased during EndMT, and that ectopic expression of miR-20a inhibits EndMT induction. TGF beta 1 induces cellular hypertrophy in human umbilical vein endothelial cells and abrogates VE-cadherin expression, reduces endothelial sprouting capacity and induces the expression of the mesenchymal marker SM22 alpha (also known as TAGLN). We identified ALK5 (also known as TGFBR1), TGFBR2 and SARA (also known as ZFYVE9) as direct miR-20a targets. Expression of miR-20a mimics abrogate the endothelial responsiveness to TGF beta 1, by decreasing ALK5, TGFBR2 and SARA, and inhibit EndMT, as indicated by the maintenance of VE-cadherin expression, the ability of the cells to sprout and the absence of SM22 alpha expression. FGF2 increases miR-20a expression and inhibits EndMT in TGF beta 1-stimulated endothelial cells. In summary, FGF2 controls endothelial TGF beta 1 signaling by regulating ALK5, TGFBR2 and SARA expression through miR-20a. Loss of FGF2 signaling combined with a TGF beta 1 challenge reduces miR-20a levels and increases endothelial responsiveness to TGF beta 1 through elevated receptor complex levels and activation of Smad2 and Smad3, which culminates in EndMT.