FGF‐VEGF crosstalk regulating vascular integrity and angiogenesis

Abstract

We have recently shown that the maintenance of vascular integrity is an active process which requires basal FGF signaling. This implies interplay of FGF and VEGF in fundamental vascular functions. In fact, numerous studies have suggested a link between FGF and VEGF signaling; however the nature of this crosstalk remains elusive. We assessed the hypothesis that FGF controls vessel growth through regulating VEGF activity. To this end, we investigated VEGF signaling in endothelial cells (EC) with disrupted FGF signaling. We found that EC lacking FGF signaling become unresponsive to VEGF due to downregulation of VEGFR2 expression caused by decreased Vegfr2 enhancer activity. This was resulted from reduced activation of Ets family transcription factors. Erk1/2 activation followed by binding of Ets proteins to the FOX:ETS composite motif in the Vegfr2 enhancer is critical to this regulation. In vivo, lack of endothelial FGF signaling manifested in the loss of vascular integrity and morphogenesis in multiple neovascularization models in mice, and impaired vessel formation caused by FGF inhibition was rescued by exogenous VEGFR2 expression. In conclusion, endothelial FGF signaling controls critical vascular functions via promoting VEGFR2 expression and thereby modifying the response to VEGF. Thus, this crosstalk accounts for the hierarchic regulation of vascular formation by FGF and VEGF. (NIH HL053793)