Sex Difference in Coronary Endothelial Dysfunction in Apolipoprotein E Knockout Mouse: Role of NO and A2A Adenosine Receptor

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Objective—Sex plays an important role in the pathophysiology of cardiovascular diseases. This study aims to investigate how sex impacts on the coronary flow regulation during atherosclerosis. Methods—ApoE KO mouse fed with western diet were used for atherosclerosis model. Coronary RH and flow response were measured using Langendorff-perfused isolated hearts. Results—Coronary RH and A23187-induced NO-dependent flow increases were significantly reduced in female (by ~28% and 48%, respectively), but not in male atherosclerotic mice. However, SNP-induced coronary vasodilation remains intact in both sexes of ApoE KO mice. LNAME (NOS inhibitor) reduced baseline flow and RH to a lesser extent in ApoE KO (by ~19% and 31%) vs. WT (~30% and 59%, respectively), and abolished the sex difference in RH. In contrast, SCH58261 (a selective A2A AR antagonist) reduced the baseline flow and RH to a greater extent in atherosclerotic mice, but did not affect the sex difference. Immunofluorescent staining of coronary arteries showed a similar A2A AR up-regulation in both sexes of ApoE KO mice. Conclusions—Our results suggest that during atherosclerosis, female mice are more susceptible to NO-dependent endothelial dysfunction and the up-regulation of A2A AR may serve as a compensatory mechanism to counteract the compromised endothelial function.