VASCULAR ENDOTHELIAL GROWTH-FACTOR INCREASES THE MITOGENIC RESPONSE TO FIBROBLAST GROWTH-FACTOR-II IN VASCULAR SMOOTH-MUSCLE CELLS IN-VIVO VIA EXPRESSION OF FMS-LIKE TYROSINE KINASE-1

Vascular endothelial growth factor (VEGF) has traditionally been consi dered an endothelial cell-specific factor inducing angiogenesis and va scular permeability in vivo. In the present study, expression of VEGF and its receptors, fetal liver kinase-1 (flk-1) and fms-like tyrosine kinase-1 (flt-1), was examined in rat carotid arteries after balloon i njury. Although VEGF and flk-1 were not detectable, high levels of flt -1 mRNA and protein were expressed by smooth muscle cells (SMCs) in th e neointima, as demonstrated by en face in situ hybridization and West ern blotting. Intimal SMC proliferation in chronically denuded rat car otid arteries was unaffected by intraluminal infusion of VEGF, whereas fibroblast growth factor (FGF)-2 with VEGF doubled the mitogenic resp onse to infused FGF-2 by increasing SMC replication in deeper layers o f the intima. VEGF increased the permeability of chronically denuded v essels to plasma proteins but had no effect on the uptake of locally i nfused biotinylated FGF-2. These findings demonstrate that vascular SM Cs express functional flt-1 receptors after arterial injury and that V EGF has synergistic effects with FGF-2 on SMC proliferation. These eff ects are likely to be mediated by a VEGF-mediated increase in permeabi lity as well as a direct interaction between the VEGF and FGF signalin g pathways.