Gender Difference in Coronary Endothelial Dysfunction in ApoE Knockout Mouse Atherosclerosis Model: Role of NO and A2A Adenosine Receptor

Abstract

Gender plays an important role in the pathophysiology of cardiovascular diseases. Coronary endothelial dysfunction is a critical stage in the pathogenesis of artherosclerosis. This study aims to investigate how gender impacts the mechanisms of coronary flow regulation in apolipoprotein E‐knockout (ApoE KO) mouse model of artherosclerosis. ApoE KO mice fed with high fat diet for 12 weeks from the age of 8 weeks were used. Coronary flow (CF) of isolated hearts was measured using Langendorff system. Coronary reactive hyperemia (RH) and A23187‐induced NO‐dependent vasodilation were significantly reduced in female (by ~28% and 48%, respectively, p<0.05) but not in male ApoE KO mice. However, sodium nitroprusside (SNP, 10‐5M)‐induced vasodilation was comparable in ApoE KO vs. WT mice in both genders. L‐NAME (100 μM) inhibited the baseline flow and coronary RH to a lesser extent in ApoE KO (by ~18.8% and 31%, respectively) than WT mice (by ~ 29.5% and 59%, respectively, p<0.05), and was less effective in inhibiting coronary RH in female ApoE KO mice (17% vs. 45% compared with male, p<0.05). Inversely, SCH58261 (a selective A2A AR antagonist, 1 μM) inhibited the baseline flow and RH to a higher extent in ApoE KO vs. WT mice, but had similar effect in both genders. Immunofluorescent staining showed a similar extent of A2A AR up‐regulation in coronary arteries of ApoE KO female vs. male animals. Our results suggest that a more severed NO‐dependent endothelial dysfunction occurs in female than male ApoE KO mice and A2A AR up‐regulation serves as a compensatory mechanism in counteracting the decreased NO‐dependent endothelial dysfunction during artherosclerosis (supported by HL027339 & HL094447).