Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis.
Systemic administration of the nitric oxide (NO) synthase inhibitor Nomega-nitro--arginine methyl ester (L-NAME) to rabbits bearing a corneal implant blocked vascular endothelial growth factor (VEGF), but not basic fibroblast growth factor (bFGF)-induced angiogenesis. L-NAME completely blocked angiogenesis induced by VEGF-transfected MCF-7 breast carcinoma cells and the cells remained dormant in the cornea. Postcapillary endothelial cell migration and growth induced by VEGF were blocked by both the NO synthase inhibitor Nomega-mono-methyl--arginine and by the guanylate cyclase inhibitor LY 83583. We conclude that NO is a downstream imperative of VEGF-, but not bFGF-induced angiogenesis, and propose that the NO synthase/guanylate cyclase pathway is a potential target for controlling tumor angiogenesis in response to VEGF. Our studies support recent evidence that VEGF and bFGF induce angiogenesis by different mechanistic pathways using the alphavbeta5 and alphavbeta3 integrins, respectively.
Ziche
M
M
Department of Pharmacology, University of Florence, 50134, Florence, Italy. ziche@stat.ds.unifi.it
Morbidelli
L
L
Choudhuri
R
R
Zhang
H T
HT
Donnini
S
S
Granger
H J
HJ
Bicknell
R
R
D000818:Animals; D003315:Cornea / Q000098:blood supply*; D016039:Corneal Transplantation; D016228:Endothelial Growth Factors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D008222:Lymphokines / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester