title: Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice.
abstract: Nucleotide P2Y2receptor (P2Y2R) contributes to vascular inflammation by increasing vascular cell adhesion molecule-1 expression in endothelial cells (EC), and global P2Y2R deficiency prevents fatty streak formation in apolipoprotein E null (ApoE-/-) mice. Because P2Y2R is ubiquitously expressed in vascular cells, we investigated the contribution of endothelial P2Y2R in the pathogenesis of atherosclerosis.
  
  
  
  EC-specific P2Y2R-deficient mice were generated by breeding VEcadherin5-Cre mice with the P2Y2R floxed mice. Endothelial P2Y2R 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 P2Y2R-deficient mice did not develop hypertension. We investigated the role of endothelial P2Y2R in the development of atherosclerotic lesions by crossing the EC-specific P2Y2R 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 P2Y2R-deficient ApoE-/-mice. Expression and proteolytic activity of matrix metalloproteinase-2 was significantly reduced in atherosclerotic lesions from EC-specific P2Y2R-deficient ApoE-/-mice. Furthermore, EC-specific P2Y2R deficiency inhibited nitric oxide production, leading to significant increase in smooth muscle cell migration out of aortic explants.
  
  
  
  EC-specific P2Y2R 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.
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.).
authors.forename: Xingjuan
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.).
authors.forename: Shaomin
authors.initials: S
authors.lastname: Qian
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.).
authors.forename: April
authors.initials: A
authors.lastname: Hoggatt
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.).
authors.forename: Hongying
authors.initials: H
authors.lastname: Tang
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.).
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.).
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Obukhov
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.).
authors.forename: Paul B
authors.initials: PB
authors.lastname: Herring
authors.affiliation: From the Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis (X.C., S.Q., A.H., H.T., A.G.O., P.B.H., C.I.S.); and Department of Medicine, University of Wisconsin-Madison (T.A.H.). cseye@iu.edu.
authors.forename: Cheikh I
authors.initials: CI
authors.lastname: Seye
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058473:Receptors, Purinergic P2Y2 / Q000172:deficiency* / Q000235:genetics; D012422:Rupture, Spontaneous; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; C546386:P2ry2 protein, mouse; D058912:Purinergic P2Y Receptor Agonists; D058473:Receptors, Purinergic P2Y2; D014665:Vasodilator Agents; D009569:Nitric Oxide; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: adenosine 5’-trisphosphate; atherosclerosis; endothelial cell; receptor; smooth muscle cell