Signaling properties of VEGF receptor-1 and-2 homo- and heterodimers

Vascular endothelial growth factor (VEGF-A) exerts its effects through rece ptor tyrosine kinases VEGF receptor-1 (VEGFR-1) and VEGFR-2, which are expr essed on most endothelial cell types in vitro and in vivo. We have examined VEGF-A-induced signal transduction in porcine aortic endothelial (PAE) cel ls individually expressing VEGFR-1 or VEGFR-2, and cells co-expressing both receptor types. We show that VEGF-A-stimulated PAE cells co-expressing VEG FR-1 and -2 contain receptor heterodimers. VEGF-A-stimulation of all three cell lines (expressing VEGFR-1, -2 and -1/2) resulted in signal transductio n with different efficiencies. Thus, tyrosine phosphorylation of phospholip ase Cy, and accumulation of inositol polyphosphates were efficiently transd uced in the VEGFR-1/2 cells whereas cells expressing VEGFR-1 responded poor ly in these assays. In contrast, VEGF-A-induced activation of phosphoinosit ide 3-kinase and induction of Ca2+ fluxes were transduced well by VEGFR-1 a nd VEGFR-2 homo- and heterodimers. The pattern of Ca2+ fluxes was unique fo r each type of VEGF receptor dimer. Our data show that signal transduction induced by VEGF-A is transduced in distinct manners by homo- and heterodime rs of VEGF receptors. (C) 2001 Elsevier Science Ltd. All rights reserved.