title: Major contribution of the P2Y₁receptor in purinergic regulation of TNFα-induced vascular inflammation.
abstract: BACKGROUND
  Atherosclerosis is an inflammatory disease, and extracellular nucleotides are one of the factors possibly involved in vascular inflammation. The P2Y(1) receptor for adenosine 5'-diphosphate has been shown to be involved in the development of atherosclerosis in apolipoprotein E--deficient mice. Our aim is to determine whether the endothelial P2Y(1) receptor plays a role in leukocyte recruitment during vascular inflammation and characterize underlying mechanisms.
  
  
  RESULTS
  We show here that the P2Y(1) receptor plays a role in leukocyte recruitment in inflamed mouse femoral arteries. Moreover, in wild-type bone marrow--transplanted chimeric P2Y(1)-deficient mice with an apolipoprotein E--deficient background, a strong reduction of adhesion molecule--dependent leukocyte recruitment was observed after local injection of tumor necrosis factor and interleukin 1β, excluding a role for the platelet or other hematopoietic cell type P2Y(1) in these events. Similarly, the in vitro adhesion of isolated mouse monocytes to tumor necrosis factor α--stimulated murine endothelial cell monolayers and their migration across the cell layers were strongly reduced in P2Y(1)-deficient compared with wild-type endothelial cells, as was the expression of the adhesion molecules P-selectin, Vascular cell adhesion molecule 1, and intercellular adhesion molecule 1. Pharmacological inhibition using the selective antagonist MRS2500 also resulted in decreased expression of adhesion molecules. These events are related to the p38 mitogen-activated protein kinase and activating transcription factor 2 pathway. Finally, in vivo administration of MRS2500 resulted in strong reduction of leukocyte recruitment in inflamed femoral arteries of apolipoprotein E--deficient mice.
  
  
  CONCLUSIONS
  The data highlight a key role of the endothelial P2Y(1) receptor in acute vascular inflammation. Pharmacological targeting the P2Y(1) receptor could represent a promising approach for the treatment of vascular inflammation.
authors.affiliation: UMR_S949 INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, Strasbourg, France.
authors.forename: Murielle
authors.initials: M
authors.lastname: Zerr
authors.forename: Béatrice
authors.initials: B
authors.lastname: Hechler
authors.forename: Monique
authors.initials: M
authors.lastname: Freund
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Magnenat
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lanois
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cazenave
authors.forename: Catherine
authors.initials: C
authors.lastname: Léon
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
mesh_terms: D000208:Acute Disease; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001167:Arteritis / Q000378:metabolism / Q000473:pathology*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D008642:Mesenteric Veins / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000502:physiology*; D018183:Transplantation Chimera; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D058472:Receptors, Purinergic P2Y1; D014409:Tumor Necrosis Factor-alpha