on May 10, 2004
Published online before print May 10, 2004, doi: 10.1161/01.CIR.0000129225.67353.1F
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Submitted on December 17, 2003
From the Cardiovascular Research Center (D.C.W., J.R.K.) and the Departments of Anesthesiology (D.C.W., N.L.L., B.M., L.M.L., P.S.P., D.C.W., J.R.K.), Pharmacology and Toxicology (L.M.L., D.C.W., J.R.K.), and Medicine (Division of Cardiovascular Diseases) (D.C.W.), Medical College of Wisconsin, Milwaukee; the Clement J. Zablocki Veterans Affairs Medical Center (P.S.P., D.C.W.), Milwaukee, Wis; and the Department of Physiology (W.M.C.), Health Science Center, Louisiana State University, New Orleans. * To whom correspondence should be addressed. E-mail: jkersten{at}mcw.edu.
Background--Development of coronary collateral vessels is impaired in patients with diabetes mellitus. We tested the hypothesis that hyperglycemia alone attenuates collateral development and abolishes proliferative properties of myocardial interstitial fluid (MIF) by enhancing expression of matrix metalloproteinases (MMP) and angiostatin. Methods and Results--Chronically instrumented dogs were randomly assigned to receive an infusion of normal saline (control; n=9) or 70% dextrose in water to increase blood glucose to 350 to 400 mg/dL for 8 h/d (hyperglycemia; n=7) in the presence or absence (sham; n=9) of brief (2 minutes), repetitive coronary artery occlusions (1/h; 8/d for 21 days). Collateral perfusion increased to 41±11% and 49±6% of normal zone flow in control dogs on days 14 and 21 (P<0.05) but remained unchanged over 21 days in hyperglycemic and sham dogs (12±3% and 13±3%, respectively). A progressive reduction of the postocclusive peak reactive hyperemic response was also observed in control dogs (16±1 to 10±1 Hz · 102 on days 1 and 21, respectively) but not in hyperglycemic (17±2 to 20±2) or sham (17±2 to 16±1) dogs. Endothelial cell tube formation was produced by MIF obtained from control dogs but not hyperglycemic or sham dogs. Coincubation of MIF from hyperglycemic dogs with an angiostatin antibody restored endothelial cell tube formation. MMP-9 activity and expression of angiostatin were increased in dogs receiving exogenous glucose compared with controls Conclusions--Chronic hyperglycemia abolishes development of coronary collateral vessels by increasing MMP-9 activity and angiostatin expression in dogs.
Revised on January 28, 2004
Accepted on February 2, 2004
Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin
Dorothee Weihrauch DVM, PhD,
Key words: angiogenesis • collateral circulation • diabetes mellitus • glucose • metalloproteinases
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