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(Circulation Research. 2006;99:140.)
© 2006 American Heart Association, Inc.

Molecular Medicine

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, York N. Hsiang, Lise A. Matzke, Bruce M. McManus, Cornelis van Breemen^*, Elena B. Okon^*

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.

Correspondence to Ada W.Y. Chung, PhD, Cardiovascular Science, Rm 2099, 950 28th W Ave, Vancouver, British Columbia V5Z 4H4, Canada. 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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