Angiostatin inhibits coronary angiogenesis during impaired production of nitric oxide. Circulation 2002 May 07;105(18):2185-91
Date
05/08/2002Pubmed ID
11994253DOI
10.1161/01.cir.0000015856.84385.e9Scopus ID
2-s2.0-0037035480 (requires institutional sign-in at Scopus site) 148 CitationsAbstract
BACKGROUND: The in vivo mechanism by which inhibition of NO synthase impairs ischemia-induced coronary vascular growth is unknown. We hypothesized that production of the growth inhibitor angiostatin increases during decreased NO production, blunting angiogenesis and collateral growth.
METHODS AND RESULTS: Measurements were made in myocardial tissue or interstitial fluid (MIF) from dogs undergoing repetitive coronary occlusions under control conditions or during antagonism of NO synthase (N(G)-nitro-L-arginine methyl ester [L-NAME]) for 7, 14, or 21 days. A sham group was instrumented identically but received no occlusions. In controls, capillary density in the ischemic zone increased initially but returned to baseline at the later times. In the L-NAME group, capillary density was lower at 7 days compared with that of controls. MIF from control dogs induced in vitro endothelial tube formation and cell proliferation, significantly greater than that from the L-NAME group. MIF from shams did not stimulate tube formation. In controls or shams, tube formation or cell proliferation did not change after administration of antiangiostatin, but this antibody restored the responses to control levels in the L-NAME group. Angiostatin expression in MIF was increased in the L-NAME group compared with controls and shams. The activities of tissue matrix metalloproteinases (MMPs) MMP-2 and MMP-9, which generate angiostatin, were increased in the L-NAME group.
CONCLUSIONS: Inhibition of NO synthase increased expression of angiostatin and activities of MMP-2 and MMP-9. Our findings indicate that angiostatin inhibits coronary angiogenesis during compromised NO production and may underscore the impairment of coronary angiogenesis during endothelial dysfunction.
Author List
Matsunaga T, Weihrauch DW, Moniz MC, Tessmer J, Warltier DC, Chilian WMMESH terms used to index this publication - Major topics in bold
Angiogenesis InhibitorsAngiostatins
Animals
Capillaries
Cell Division
Cells, Cultured
Collateral Circulation
Coronary Circulation
Dogs
Endothelium, Vascular
Extracellular Space
Female
Humans
Kinetics
Male
Matrix Metalloproteinases
Myocardial Ischemia
NG-Nitroarginine Methyl Ester
Neovascularization, Physiologic
Nitric Oxide
Nitric Oxide Synthase
Peptide Fragments
Plasminogen
