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PMID: 7517330 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Evidence that nitric oxide is an endogenous antiangiogenic mediator.

British journal of pharmacology ·Vol. 111 ·No. 3 ·1994-03-00 ·Pages 894-902

Pipili-Synetos E, Sakkoula E, Haralabopoulos G, Andriopoulou P, Peristeris P, Maragoudakis ME

Abstract

1. The involvement of nitric oxide (NO) in the regulation of angiogenesis was examined in the in vivo system of the chorioallantoic membrane (CAM) of the chick embryo and in the matrigel tube formation assay. 2. Sodium nitroprusside (SNP) (0.37-28 nmol/disc), which releases NO spontaneously, caused a dose-dependent inhibition of angiogenesis in the CAM in vivo and reversed completely the angiogenic effects of alpha-thrombin (6.7 nmol/disc) and the protein kinase C (PKC) activator 4-beta-phorbol-12-myristate-13-acetate (PMA) (0.97 nmol/disc). In addition, SNP (28 x 10(-6) M) stimulated the release of guanosine 3'-5'-cyclic monophosphate (cyclic GMP) from the CAM in vitro. 3. In the matrigel tube formation assay, an in vitro assay of angiogenesis, both SNP (1-3 x 10(-6) M) and the cell permeable cyclic GMP analogue, Br-cGMP (0.3-1.0 x 10(-3) M) reduced tube formation. 4. The inhibitors of NO synthase, NG-monomethyl-L-arginine (L-NMMA) (3.8-102 nmol/disc) and NG-nitro-L-arginine methylester (L-NAME) (1.3-34.2 nmol/disc) stimulated angiogenesis in the CAM in vivo, in a dose-dependent fashion. D-NMMA and D-NAME on the other hand had no effect on angiogenesis in this system. 5. L-Arginine (10.9 nmol/disc), although it had a modest antiangiogenic effect by itself, was capable of abolishing the angiogenic effects of L-NMMA (34.2 nmol/disc) and of L-NAME (3.8 nmol/disc). 6. Dexamethasone, an inhibitor of the induction of NO synthase, at 0.2-116.1 nmol/disc, stimulated angiogenesis in the CAM, whereas at 348.4-1161 nmol/disc it inhibited this process. Combination of 38.7 nmol/disc dexamethasone with L-NAME (9.3 nmol/disc) resulted in a potentiation of the angiogenic effect of the former. It appears therefore that both the constitutive and the inducible NO synthase may contribute to the NO-mediated inhibition of angiogenesis. 7. Superoxide dismutase (SOD), which prevents the destruction of NO, at 300 i.u./disc had a modest antiangiogenic effect in the CAM, by itself. In addition, SOD, prevented alpha-thrombin (6.7 nmol/disc) and PMA (0.97 nmol/disc) from stimulating angiogenesis in the CAM.8. These results suggest that NO may be an endogenous antiangiogenic molecule of pathophysiological importance.

MeSH Terms
Allantois/drug effects,physiology Animals Arginine/analogs & derivatives,antagonists & inhibitors,biosynthesis,pharmacology Chick Embryo Chorion/drug effects,physiology Cyclic GMP/analogs & derivatives,biosynthesis,pharmacology Dexamethasone/pharmacology Drug Interactions Endothelium, Vascular/cytology Humans Models, Biological NG-Nitroarginine Methyl Ester Neovascularization, Pathologic/physiopathology Nitric Oxide/antagonists & inhibitors,physiology Nitroprusside/pharmacology Superoxide Dismutase/pharmacology Tetradecanoylphorbol Acetate/pharmacology Thrombin/antagonists & inhibitors,pharmacology omega-N-Methylarginine
Chemicals
Nitroprusside omega-N-Methylarginine 8-bromocyclic GMP Nitric Oxide Dexamethasone Arginine Superoxide Dismutase Thrombin Cyclic GMP Tetradecanoylphorbol Acetate NG-Nitroarginine Methyl Ester
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Pipili-Synetos E
Department of Pharmacology, Medical School, University of Patras, Greece.
Sakkoula E
Haralabopoulos G
Andriopoulou P
Peristeris P
Maragoudakis M E
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1111/j.1476-5381.1994.tb14822.x
Published
1994-03-00
Pages
894-902
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1910111
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1476-5381.1994.tb14822.x PMC Full Text View journal details
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