Knockout mice reveal a role for P2Y6 receptor in macrophages, endothelial cells, and vascular smooth muscle cells.
P2Y receptors are G-protein-coupled receptors activated by extracellular nucleotides. The P2Y(6) receptor is selectively activated by UDP, and its transcript has been detected in numerous organs, including the spleen, thymus, intestine, blood leukocytes, and aorta. To investigate the biological functions of this receptor, we generated P2Y(6)-null mice by gene targeting. The P2Y(6) knockout (KO) mice are viable and are not distinguishable from the wild-type (WT) mice in terms of growth or fertility. In thioglycollate-elicited macrophages, the production of inositol phosphate in response to UDP stimulation was lost, indicating that P2Y(6) is the unique UDP-responsive receptor expressed by mouse macrophages. Furthermore, the amount of interleukin-6 and macrophage-inflammatory protein-2, but not tumor necrosis factor-alpha, released in response to lipopolysaccharide stimulation was significantly enhanced in the presence of UDP, and this effect was lost in the P2Y(6) KO macrophages. The endothelium-dependent relaxation of the aorta by UDP was abolished in KO P2Y(6) mice. The contractile effect of UDP on the aorta, observed when endothelial nitric-oxide synthase is blocked, was also abolished in P2Y(6)-null mice. In conclusion, we generated P2Y(6)-deficient mice and have shown that these mice have a defective response to UDP in macrophages, endothelial cells, and vascular smooth muscle cells. These observations might be relevant to several physiopathological conditions such as atherosclerosis or hypertension.
Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine, Universite' Libre de Bruxelles, Gosselies, Belgium.
Isabelle
I
Bar
Pieter-Jan
PJ
Guns
Jessica
J
Metallo
Dorothée
D
Cammarata
Françoise
F
Wilkin
Jean-Marie
JM
Boeynams
Hidde
H
Bult
Bernard
B
Robaye
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D007295:Inositol Phosphates / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009711:Nucleotides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D013864:Thioglycolates / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects
D016207:Cytokines; D007295:Inositol Phosphates; D008070:Lipopolysaccharides; D009711:Nucleotides; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D013864:Thioglycolates; C099845:purinoceptor P2Y6; D010656:Phenylephrine; D048049:Extracellular Signal-Regulated MAP Kinases