Abstract 606: Pharmacological Inhibition of PAI-1 Rescues Blood Flow Perfusion Through Promoting Capillary Arterialization in Diabetic Microangiopathy in Ischemic Limb

Abstract

OBJECTIVE: 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 microvascular disease is poorly defined. RESEARCH DESIGN AND METHODS: 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 to determine if PAI-1 attenuates neovasculature formation in DM mice. RESULTS: 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 and ischemic muscles PAI-1 levels in the DM group. Pharmacologic inhibition of PAI-1 with PAI-039 rescued the ischemia-mediated impairments in blood flow perfusion and accelerated arterialization of capillaries in ischemic muscles in DM group compared to vehicle-DM group. Immunohistochemical analysis indicated increased expression of smooth muscle α-actin on capillary-sized vessels, and increased infiltration by CD45 leukocytes in ischemic gastrocnemius muscle tissues of PAI-1 inhibitor-treated mice. Furthermore, in these mice, VEGF-A was significantly down-regulated, and conversely, the expression of the PDGF-B and MMP 2, 9 were up-regulated in ischemic muscles in the inhibition of PAI-1 after induced ischemia. CONCLUSIONS: Taken together, these findings illustrate that the pharmacologic inhibition of elevated PAI-1 rescues the impairments in ischemia-mediated flow perfusion and capillary arterializations observed in DM, and may have efficacy as a therapeutic strategy to prevent diabetic microangiopathy.