Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice

Xingjuan Chen, Shaomin Qian, April Hoggatt, Hongying Tang, Timothy A Hacker, Alexander G Obukhov, Paul B Herring, Cheikh I Seye
Arteriosclerosis, Thrombosis, and Vascular Biology 2017, 37 (1): 75-83

OBJECTIVE: Nucleotide P2Y2 receptor (P2Y2 R) contributes to vascular inflammation by increasing vascular cell adhesion molecule-1 expression in endothelial cells (EC), and global P2Y2 R deficiency prevents fatty streak formation in apolipoprotein E null (ApoE-/- ) mice. Because P2Y2 R is ubiquitously expressed in vascular cells, we investigated the contribution of endothelial P2Y2 R in the pathogenesis of atherosclerosis.

APPROACH AND RESULTS: EC-specific P2Y2 R-deficient mice were generated by breeding VEcadherin5-Cre mice with the P2Y2 R floxed mice. Endothelial P2Y2 R deficiency reduced endothelial nitric oxide synthase activity and significantly altered ATP- and UTP (uridine 5'-triphosphate)-induced vasorelaxation without affecting vasodilatory responses to acetylcholine. Telemetric blood pressure and echocardiography measurements indicated that EC-specific P2Y2 R-deficient mice did not develop hypertension. We investigated the role of endothelial P2Y2 R in the development of atherosclerotic lesions by crossing the EC-specific P2Y2 R knockout mice onto an ApoE-/- background and evaluated lesion development after feeding a standard chow diet for 25 weeks. Histopathologic examination demonstrated reduced atherosclerotic lesions in the aortic sinus and entire aorta, decreased macrophage infiltration, and increased smooth muscle cell and collagen content, leading to the formation of a subendothelial fibrous cap in EC-specific P2Y2 R-deficient ApoE-/- mice. Expression and proteolytic activity of matrix metalloproteinase-2 was significantly reduced in atherosclerotic lesions from EC-specific P2Y2 R-deficient ApoE-/- mice. Furthermore, EC-specific P2Y2 R deficiency inhibited nitric oxide production, leading to significant increase in smooth muscle cell migration out of aortic explants.

CONCLUSIONS: EC-specific P2Y2 R deficiency reduces atherosclerotic burden and promotes plaque stability in ApoE-/- mice through impaired macrophage infiltration acting together with reduced matrix metalloproteinase-2 activity and increased smooth muscle cell migration.

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