Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells

Vascular endothelial growth factor (VEGF) intracellular signaling in endoth elial cells is initiated by the activation of distinct tyrosine kinase rece ptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1/KDR). Because the tyrosine kinase-d ependent transcription factors known as STAT (signal transducers and activa tors of transcription) proteins are important modulators of cell growth res ponses induced by other growth factor receptors, we have determined the eff ects VEGF of on STAT activation in BAEC (bovine aortic endothelial cells). Here, we show that VEGF induces tyrosine phosphorylation and nuclear transl ocation of STAT1 and STAT6. VEGF also stimulates STAT3 tyrosine phosphoryla tion, but nuclear translocation does not occur. We found that placenta grow th factor, which selectively activates VEGFR1, has no effect on the STATs. However, upon VEGF stimulation, STAT1 associates with the VEGFR2 in a tyros ine kinase-dependent manner, indicating that VEGF-induced STAT1 activation is mediated primarily by VEGFR2. Thus, our study shows for the first time t hat VEGF activates the STAT pathway through VEGFR2. Because the growth-prom oting activity of VEGF depends upon VEGFR2 activation, these findings sugge st a role for the STATs in the regulation of gene expression associated wit h the angiogenic effects of VEGF.