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Evidence that nitric oxide is an endogenous antiangiogenic mediator.

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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

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

doi

10.1111/j.1476-5381.1994.tb14822.x

subject

Has Abstract

pub_date

1994-03-01 00:00:00

pages

894-902

issue

eissn

0007-1188

issn

1476-5381

journal_volume

111

pub_type

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Evidence that nitric oxide is an endogenous antiangiogenic mediator.