VEGF induces NO-dependent hyperpermeability in coronary venules.
The purpose of this study was to investigate the direct effect of vascular endothelial growth factor (VEGF) on microvascular permeability and its signaling mechanisms. The apparent permeability coefficient to albumin was measured in isolated coronary venules. Topical application of VEGF dose-dependently and transiently increased albumin permeability by two- to threefold. Inhibition of nitric oxide (NO) synthesis with NG-monomethyl-L-arginine abolished VEGF-induced venular hyperpermeability. Furthermore, because NO exerts vasoactive effects through stimulation of guanylate cyclase (GC) and the subsequent production of guanosine 3',5'-cyclic monophosphate (cGMP), we examined the role of GC and cGMP-dependent protein kinase (PKG) in the mediation of VEGF's action. The permeability response to VEGF was measured in the presence of the selective GC inhibitor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one and the specific PKG inhibitor KT-5823. Both inhibitors reduced basal permeability and prevented the hyperpermeability response to VEGF. Therefore, we suggest that VEGF modulates microvascular permeability via a signaling cascade involving NO synthesis, GC stimulation, and PKG activation.
Wu
H M
HM
Microcirculation Research Institute, Texas A&M University Health Science Center, Temple 76504, USA.
Huang
Q
Q
Yuan
Y
Y
Granger
H J
HJ
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D002227:Carbazoles; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007211:Indoles; D008222:Lymphokines / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014699:Venules / Q000187:drug effects / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000470:Alkaloids; D002227:Carbazoles; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C073601:KT 5823; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase