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.
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.
Chung
Ada W Y
AW
The James Hogg iCAPTURE Center for the Cardiovascular and Pulmonary Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada. achung@mrl.ubc.ca
Hsiang
York N
YN
Matzke
Lise A
LA
McManus
Bruce M
BM
van Breemen
Cornelis
C
Okon
Elena B
EB
D000368:Aged; D043168:Angiostatins / Q000235:genetics*; D001158:Arteries / Q000201:enzymology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000503:physiopathology*; D003925:Diabetic Angiopathies; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9