Vascular endothelial growth factor increases the mitogenic response to fibroblast growth factor-2 in vascular smooth muscle cells in vivo via expression of fms-like tyrosine kinase-1.
Vascular endothelial growth factor (VEGF) has traditionally been considered an endothelial cell-specific factor inducing angiogenesis and vascular 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 injury. Although VEGF and flk-1 were not detectable, high levels of flt-1 mRNA and protein were expressed by smooth muscle cells (SMCs) in the neointima, as demonstrated by en face in situ hybridization and Western blotting. Intimal SMC proliferation in chronically denuded rat carotid arteries was unaffected by intraluminal infusion of VEGF, whereas fibroblast growth factor (FGF)-2 increased the number of replicating SMCs 4-fold. Pretreatment with VEGF doubled the mitogenic response to infused FGF-2 by increasing SMC replication in deeper layers of the intima. VEGF increased the permeability of chronically denuded vessels to plasma proteins but had no effect on the uptake of locally infused biotinylated FGF-2. These findings demonstrate that vascular SMCs express functional flt-1 receptors after arterial injury and that VEGF has synergistic effects with FGF-2 on SMC proliferation. These effects are likely to be mediated by a VEGF-mediated increase in permeability as well as a direct interaction between the VEGF and FGF signaling pathways.
Couper
L L
LL
Maine Medical Center Research Institute, South Portland, Me 04106, USA.
Bryant
S R
SR
Eldrup-Jørgensen
J
J
Bredenberg
C E
CE
Lindner
V
V
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000032:analysis / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D008222:Lymphokines / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000032:analysis; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1