Genetic Deletion of P2Y 2 Receptor Induces Vascular Endothelial Dysfunction but not Large Artery Stiffening in Mice

Abstract

The G-protein coupled and UTP/ATP-sensitive P2Y2 receptor has been linked to production of nitric oxide (NO) and prostaglandins in numerous cell types including endothelial and vascular smooth muscle cells. We hypothesized that genetic deletion of P2Y2 would induce generalized dysfunction in arteries. We measured endothelium dependent dilation to acetylcholine (ACh) in the presence or absence of the NO inhibitor, L-NAME, in large central (carotid) and small peripheral (gastrocnemius feed) arteries (N = 15) isolated from 5 – 8 months old P2Y2 deficient (-/-) or wild type (WT) mice. Maximal vasodilation to ACh was blunted in both carotid (Car) and gastrocnemius (Gas) feed arteries in the P2Y2 -/- compared to WT (Car: 88 ± 1 vs. 97 ± 2%; Gast: 86 ± 3 vs. 97 ± 2%; both p<0.05). L-NAME significantly reduced vasodilation in arteries from both groups (p<0.05), but abolished differences between P2Y2-/- and WT, indicating blunted NO dependent dilation in P2Y2-/- arteries. Smooth muscle function, assessed by dilation to sodium nitroprusside, was similar between P2Y2-/- and WT (Car: 98 ± 1 vs. 95 ± 2%; Gast: 91 ± 3 vs. 90 ± 2%; both p>0.05). Despite endothelial dysfunction in P2Y2-/- mice, in vivo large artery stiffness assessed via pulse wave velocity was similar between groups (p>0.05). Thus, deletion of the P2Y2 receptor induces endothelial dysfunction and reduces NO bioavailability in large and small arteries but does not impact smooth muscle vasodilation or large artery stiffness.