Divergent coronary flow responses to uridine adenosine tetraphosphate in atherosclerotic ApoE knockout mice.

Uridine adenosine tetraphosphate (UpA) exerts potent relaxation in porcine coronary arteries that is reduced following myocardial infarction, suggesting a crucial role for UpA in the regulation of coronary flow (CF) in cardiovascular disorders. We evaluated the vasoactive effects of UpA on CF in atherosclerosis using ApoE knockout (KO) mice ex vivo and in vivo. Functional studies were conducted in isolated mouse hearts using the Langendorff technique. Immunofluorescence was performed to assess purinergic P2X receptor (P2XR) expression in isolated mouse coronary arteries. In vivo effects of UpA on coronary blood flow (CBF) were assessed using ultrasound. Infusion of UpA (10-10 M) into isolated mouse hearts resulted in a concentration-dependent reduction in CF in WT and ApoE KO mice to a similar extent; this effect was exacerbated in ApoE KO mice fed a high-fat diet (HFD). The P2XR antagonist MRS2159 restored UpA-mediated decreases in CF more so in ApoE KO + HFD than ApoE KO mice. The smooth muscle to endothelial cell ratio of coronary P2XR expression was greater in ApoE KO + HFD than ApoE KO or WT mice, suggesting a net vasoconstrictor potential of P2XR in ApoE KO + HFD mice. In contrast, UpA (1.6 mg/kg) increased CBF to a similar extent among the three groups. In conclusion, UpA decreases CF more in ApoE KO + HFD mice, likely through a net upregulation of vasoconstrictor P2XR. In contrast, UpA increases CBF in vivo regardless of the atherosclerotic model.