Abstract P738: Matrix Metalloproteinase-3 (mmp3) Activation Impairs Endothelial Integrity and Increases Vascular Injury After Ischemic Stroke in Female Diabetic Rats

Abstract

Introduction: Females patients with diabetes suffer from poor outcomes of ischemic stroke but underlying reasons are not fully understood. We have shown that 1) adult female diabetic rats develop greater infarct and hemorrhagic transformation (HT) leading to poorer outcomes after ischemic stroke, and 2) MMP3 activity is increased to a greater extent in female endothelial cells as well as the microvasculature of diabetic female rats than in males. This led us to hypothesize that MMP3 mediates disruption of endothelial integrity amplifying vascular injury in female diabetic rats. Methods: Diabetic female Wistar rats, subjected to 60 min MCAO, received a single dose of MMP3 inhibitor (UK356618; 15mg/kg; iv) or vehicle after reperfusion. On Day 3, adhesive removal time (ART), behavioral composite score, brain infarct size, edema and macroscopic HT were recorded. Primary brain microvascular endothelial cells (BMVECs) isolated from female rats were cultured in 25mM glucose plus 100μM sodium palmitate for 48 hours followed by hypoxia insult for 24 hours in the presence/absence of UK356618 (20nM). Endothelial phenotype and integrity were assessed. Results: Brain edema and HT scores were lower and outcomes were improved with MMP3 inhibition but infarct size was not different between the groups (Table). Hypoxia decreased tight junction protein occludin-1 while increasing transforming growth factor receptor-1 (TGF-R1), a key modulator of endothelial phenotype. Treatment with inhibitor UK356618 reversed these responses. Conclusions: The lack of a difference in infarct size with the treatment suggests that MMP3 inhibition improves short term outcomes in female diabetic rats via preservation of endothelial integrity. The decrease in TGF-R1 needs to be further investigated for long term effects of MMP3 inhibition on vascular restoration and recovery after stroke in diabetes.