Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells

Vascular endothelial growth factor (VEGF) provokes angiogenesis in vivo and stimulates growth and differentiation of endothelial cells in vitro. Altho ugh VEGF receptor-1 (VEGFR-1) and VEGFR-2 are known to be high affinity rec eptors for VEGF, it is not clear which of the VEGFRs are responsible for th e transmission of the diverse biological responses of VEGF. For this purpos e we have constructed a chimeric receptor for VEGFR-1 (CTR) and VEGFR-2 (CK R) in which the extracellular domain of each receptor was replaced with the extracellular domain of human colony-stimulating factor-1 receptor (CSF-1R ), and these receptors were expressed in pig aortic endothelial (PAE) cells . We show that CHR individually expressed in PAE cells is readily tyrosine- phosphorylated in vivo, autophosphorylated in vitro, and stimulates cell pr oliferation in a CSF-1-dependent manner. In contrast, CTR individually expr essed in PAE cells showed no significant in vivo, in vitro tyrosine phospho rylation and cell growth in response to CSF-1 stimulation. The kinase activ ity of CKR was essential for its biological activity, since mutation of lys ine 866 to arginine abolished its in vivo, in vitro tyrosine phosphorylatio n and mitogenic signals. Remarkably, activation of CTR repressed CKR-mediat ed mitogen-activate protein kinase activation and cell proliferation. Simil ar effects were observed for VEGFR-2 co-expressed with VEGFR-1. Collectivel y, these findings demonstrate that VEGFR-8 activation plays a positive role in angiogenesis by promoting endothelial cell proliferation In contrast, a ctivation of VEGFR-1 plays a stationary role in angiogenesis by antagonizin g VEGFR-2 responses.