Published online before print June 15, 2006, doi: 10.1161/01.RES.0000232352.90786.fa
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Submitted on January 27, 2006
Revised on May 17, 2006
Accepted on June 5, 2006
Reduced Expression of Vascular Endothelial Growth Factor Paralleled With the Increased Angiostatin Expression Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in Human Type 2 Diabetic Arterial Vasculature
Ada W.Y. Chung *;
From The James Hogg iCAPTURE Center for the Cardiovascular and Pulmonary Research (A.W.Y.C., L.A.M., B.M.M, C.V.B., E.B.O.), St. Paul’s Hospital, University of British Columbia; Children and Family Research Institute (A.W.Y.C., C.V.B.) and Department of Surgery (Y.N.H.), University of British Columbia, Vancouver, Canada.
* To whom correspondence should be addressed. E-mail: achung{at}mrl.ubc.ca.
Impaired angiogenesis could contribute to the increased incidence of coronary and peripheral artery disease in diabetic patients. Angiogenesis is initiated by vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, and suppressed by angiostatin, which is generated by matrix metalloproteinase (MMP)-2 and -9 through proteolytic cleavage of plasminogen. We hypothesized that MMP-2 and -9 were upregulated in the diabetic vasculature, resulting in increased angiostatin production and reduced blood vessel formation. In diabetic internal mammary artery samples (n=32) collected from patients undergoing coronary artery bypass grafting surgery, capillary density was only 30% of that in the nondiabetic vessels (n=32), whereas VEGF expression was reduced by 48%. Diabetes upregulated the expression and the gelatinolytic activity of MMP-2 and -9. Active MMP-2 and -9 were released from diabetic arteries, but not from nondiabetic vessels, during phenylephrine-induced vasoconstriction. Diabetes enhanced transcription and protein expression of tissue inhibitor of MMP (TIMP)-1 but had an opposite effect on TIMP-2. In diabetic vessels angiostatin was increased by 62% and was positively correlated with the activities of MMP-2 and -9 (r2=0.806 and 0.742, respectively). This report indicated a strong correlation between the upregulation of MMP-2 and MMP-9 and the increased angiostatin expression in the human diabetic arterial vasculature. The enhanced angiostatin production with a reduced VEGF formation may explain the pathogenesis of impaired angiogenesis in diabetes mellitus.
Key words: matrix metalloproteinase • angiostatin • angiogenesis • type 2 diabetes • vascular endothelial growth factor
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