PLASMINOGEN-ACTIVATOR INHIBITOR-1 EXPRESSION BY BRAIN MICROVESSEL ENDOTHELIAL-CELLS IS INHIBITED BY ELEVATED GLUCOSE

Patients with diabetes are predisposed to microvascular disease. In th e retina and brain, this is characterized by neovascularization and ne w capillary formation. Because of the potential importance of plasmin generation in these processes, we evaluated the effect of elevated glu cose concentrations on expression of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and urokinase (uPA) in c ultured bovine brain endothelial cells (BBEC) versus cultured bovine a ortic endothelial cells (BAEC). We observed that BBEC PAI-1 mRNA level s were decreased fivefold in cells cultured in media containing 20 mM glucose compared with BBEC cultured in media with 5.5 mM glucose, wher eas expression of PAI-1 mRNA in BAEC, bovine mesenteric endothelial ce lls, and human umbilical vein endothelial cells was not modulated unde r these conditions. Expression of PAI-1 protein was also inhibited by growth of BBEC in elevated glucose, but the effect was less marked tha n at the mRNA level. Elevated glucose did not decrease expression of P AI-1 protein by BAEC. Withdrawal of acidic fibroblast growth factor en hanced expression of PAI-1 mRNA and protein in BBEC. Expression of tPA mRNA was not affected by the glucose concentration of the medium, and uPA mRNA was not detected in our BBEC cultures. A decrease in the loc al tissue activity of PAI-1 by elevated glucose concentrations, with n o effect on tPA or uPA expression, would lead to an increase in the pl asmin activity and thereby predispose neural tissues, such as the cere brum and retina, of diabetic patients to neovascularization.