KDR (VEGF receptor 2) is the major mediator for the hypotensive effect of VEGF.
Vascular endothelial growth factor (VEGF) exerts vasodilation-induced hypotension as a major side effect for treatment of ischemic diseases. VEGF has 2 receptor tyrosine kinases, KDR and Flt-1. Little is known about which receptor mediates VEGF-induced hypotension. To elucidate the role of each receptor in mediating hypotension, KDR-selective and Flt-1-selective mutants were used for in vitro and in vivo studies. The KDR-selective mutant induced vascular endothelial cell proliferation comparable to VEGF, whereas the Flt-1- selective mutant had no effect on proliferation. Intravenous injection of KDR-selective mutant, Flt-selective mutant, or VEGF caused a dose-related decrease in mean arterial pressure in conscious rats. The hypotensive response to KDR-selective mutant was significantly less than that to VEGF (P<0.01) but was greater than that to Flt-selective mutant (P<0.01). Similarly, VEGF and KDR-selective mutant induced more potent vasorelaxation than Flt-selective mutant or placenta growth factor that binds Flt-1 only (P<0.01), and the vasorelaxation to KDR-selective mutant was not significantly different at low concentrations but less than that to VEGF at high concentrations. The results indicate that the vasodilation and hypotensive effect of VEGF may involve both receptors, but KDR is the predominant receptor mediating this effect. Because KDR-selective mutant induced proliferation and angiogenesis similar to VEGF but was associated with 36% attenuation in hypotension, the data suggest that the KDR-selective mutant may represent an alternative treatment for ischemic diseases.
Li
Bing
B
Department of Cardiovascular Research, Genentech, Inc, South San Francisco, Calif 94080, USA.
Ogasawara
Annie K
AK
Yang
Renhui
R
Wei
Wei
W
He
Guo-Wei
GW
Zioncheck
Thomas F
TF
Bunting
Stuart
S
de Vos
Abraham M
AM
Jin
Hongkui
H
D000818:Animals; D001011:Aorta / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007022:Hypotension / Q000209:etiology* / Q000503:physiopathology; D008222:Lymphokines / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology*
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014665:Vasodilator Agents; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1