Dual actions of nitric oxide on angiogenesis: possible roles of PKC, ERK, and AP-1.
Regulation of angiogenesis by nitric oxide (NO) is controversial since NO has been shown to have both pro- and anti-angiogenic effects. In this study, we examined the effect of the NO donor, S-nitro-N-acetyl-penicillamine (SNAP), on in vitro angiogenesis, and the mechanisms involved: PKC activity, ERK and c-Jun phosphorylation, and AP-1 DNA binding activity, in microvascular endothelial cells. SNAP, at 0.5-4 mM, significantly and dose-dependently inhibited angiogenesis, PKC activity, and ERK and c-Jun phosphorylation up to 80%, 83%, and 63% and 73%, respectively. SNAP at concentrations > 2mM also abolished AP-1 binding activity. Lower concentrations of SNAP (0.1-0.3 mM) significantly increased angiogenesis, PKC activity, and ERK and c-Jun phosphorylation up to 46%, 60%, and 61% and 180%, respectively. These findings indicate that the dual pro- and anti-angiogenic actions of NO are dose-dependent and suggest that they are mediated by PKC and ERK acting on AP-1.
Jones
Michael K
MK
Department of Medicine, Veterans Affairs Medical Center, 5901 East Seventh Street, Long Beach, CA 90822, USA. michael.jones4@med.va.gov
Tsugawa
Kouji
K
Tarnawski
Andrzej S
AS
Baatar
Dolgor
D
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D008833:Microcirculation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013270:Stomach / Q000098:blood supply / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D020030:Nitric Oxide Donors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D004247:DNA; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases