Regulation of angiogenesis by controlling VEGF receptor

The endothelial cells cultured in collagen gel caused upregulation of KDR expression, which resulted in an increase in tube formation. Endothelial cells exposed to high glucose (33 mmol/l) for 30 days increased the tube formation induced by VEGF, but not by serum and bFGF. Immunohistochemical study showed that KDR expression was upregulated by the high-glucose treatment. The endothelial cells treated with 0.5-5 micrograms/ml eicosapentaenoic acid (EPA, 20:5, n-3) for 48 h displayed a dose-dependent suppression of tube formation, VEGF-induced proliferation, and activation of p42/p44 MAP kinase but not bFGF-induced ones. Pretreatment with arachidonic acid (20:4, n-6) and docosahexaenoic acid (22:6, n-3) did not show such effects. The expression of KDR was downregulated by the EPA pretreatment. The bone is the richest tissue in microvessel networks except for the liver. Osteoblasts produced VEGF and some factor(s) that could induce KDR upregulation in endothelial cells and could enhance tube formation. These results lead to the speculation that the regulation of KDR expression as well as VEGF production is deeply involved in angiogenesis under various conditions.