Impaired proliferation of endothelial cells (EC) from diabetic BB rats.
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Angiogenesis is an integral part of wound healing and individuals with diabetes exhibit significant delays in this process. We have investigated the proliferation rate of microvascular EC isolated from the spontaneously diabetic BB rat (an animal model for human type I diabetes mellitus). Diabetic (BBd) rats (25-30 days post onset of diabetes) and age-matched nondiabetesprone normal (BBn) rats were used in this study. When cultured in the presence of 10% fetal bovine serum (FBS), BBd-EC exhibited a significantly slower proliferation rate and a decreased density at confluence when compared to BBn-EC. The rate of production of nitrite plus nitrate (a measure of nitric oxide [NO] production) by BBd-EC was only 15% that of the BBn-EC although arginine uptake, NO synthase activity (in the presence of optimal substrate concentrations) and intracellular arginine concentrations did not differ. The deficiency in NO production could be corrected by the addition of 10 M sepiapterin to the culture medium suggesting that tetrahydrobiopterin (a cofactor for NO synthase) availability differed in these two cell types. Sepiapterin increased the rate of proliferation of both BBd-EC and BBn-EC, suggesting a possible role for NO in the proliferation of EC. Arginase and omithine decarboxylase (ODC) activities in the BBdEC were only 10% of that of the BBn-EC suggesting that both substrate availability and polyamine production were also deficient in the diabetic animals. ODC activity in the BBd-EC was increased in the presence of 20% FBS but was still only 40-50% of that of the BBn-EC. These data suggest that-NO and polyamines are important regulators of EC proliferation and their production is deficient in spontaneously diabetic rats. (Supported by AHA grant-in-aid #95009150 and #95013030).
