Abstract 12241: Pharmacological Inhibition of PAI-1 Rescues the Defect in Ischemia-Induced Neovasculature in Type II Diabetic Mice

Background: Type II diabetes mellitus (DM) leads to the development of microvascular diseases and is associated with impaired angiogenesis. Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with DM. However, the role of PAI-1 in the development of DM-associated vascular disease is poorly defined. Methods and Results: Hind-limb ischemia was generated by femoral artery occlusion in diet-induced diabetic mice and age-matched normal chow (NC)-fed mice. Plasma was analyzed for glucose, non-esterified fatty acids, and PAI-1. PAI-039, a specific, small molecule pharmacological inhibitor of PAI-1, was orally administered to mice (1 mg/kg, twice daily for 14 days) to determine if PAI-1 attenuates neovasculature formation in DM mice. PAI-1 activity and antigen were significantly increased within 2 weeks of DM onset and remained elevated throughout the experimental period. PAI-039 normalizes elevated plasma PAI-1 activity in the DM group. Color Laser Doppler showed that the blood flo...