FGF-2 inhibits Endothelial-Mesenchymal Transition through microRNA-20a-mediated repression of canonical TGF-β Signaling

Abstract

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 TGFβ1 and changes endothelial microRNA expression. We found that miR-20a is decreased during EndMT and ectopic expression of miR-20a inhibits EndMT induction. TGFβ1 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 SM22α. We identified ALK5, TGFBR2 and SARA as direct miR-20a targets. Expression of miR-20a mimics abrogates the endothelial responsiveness to TGFβ1 by decreasing ALK5, TGFBR2, and SARA and inhibits EndMT, indicated by the maintenance of VE-Cadherin expression and sprouting ability and absence of SM22α expression. FGF2 increases miR-20a expression and inhibits EndMT in TGFβ1-stimulated endothelial cells. In summary, FGF2 controls endothelial TGFβ1 signaling by regulating ALK5, TGFBR2 and SARA expression, through miR-20a. Loss of FGF2 signaling combined with a TGFβ1 challenge reduces miR-20a levels and increases endothelial responsiveness to TGFβ1 through elevated receptor complex levels and activation of Smad2/3, which culminates in EndMT.