EFFECTS OF HIGH GLUCOSE ON VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION IN VASCULAR SMOOTH-MUSCLE CELLS

Vascular endothelial growth factor (VEGF), in addition to its growth-p romoting effects on endothelial cells, can also increase vascular perm eability and monocyte migration. It has therefore been implicated in t he pathogenic neovascularization associated with diabetic retinopathy and atherosclerosis. However, the factors regulating VEGF expression i n the vascular wall are not fully understood. In this study, we examin ed the regulation of VEGF expression in vascular smooth muscle cells ( VSMC) by hyperglycemia as well as by angiotensin II (ANG II). We also examined whether the 12-lipoxygenase (12-LO) product 12-hydroxyeicosat etraenoic acid (12-HETE) can alter VEGF expression, since 12-LO produc ts of arachidonic acid have angiogenic properties, and ANG II as well as high glucose (HG, 25 mM) can increase 12-LO activity and expression in VSMC. Studies were carried out in human (HSMC) or porcine VSMC (PS MC), which were cultured for at least two passages under normal glucos e (NG, 5.5 mM) or HG conditions. HG culture alone increased the expres sion of VEGF mRNA and protein in both HSMC and PSMC. Furthermore, ANG II treatment significantly induced VEGF mRNA and protein expression on ly in VSMC cultured in HG and not NG. In addition, 12-HETE significant ly increased VEGF mRNA and protein expression in HSMC cultured in NG a s well as in HG. Cells cultured in HG also secreted significantly grea ter amounts of VEGF into the culture medium. These results suggest tha t elevated VEGF production under HG conditions may play a role in the accelerated vascular disease observed in diabetes.