QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.046904v1 74/3/777    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bar, I. Articles by Robaye, B. PubMed PubMed Citation Articles by Bar, I. Articles by Robaye, B.

Knockout Mice Reveal a Role for P2Y₆ Receptor in Macrophages, Endothelial Cells, and Vascular Smooth Muscle Cells

Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine, Université Libre de Bruxelles, Gosselies, Belgium (I.B., J.M., D.C., F.W., J.-M.B., B.R.); Department of Clinical Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium (J.-M.B.); and Division of Pharmacology, University of Antwerp, Wilrijk, Belgium (P.-J.G., H.B.)

P2Y receptors are G-protein-coupled receptors activated by extracellular nucleotides. The P2Y₆ 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 P2Y₆-null mice by gene targeting. The P2Y₆ 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 P2Y₆ 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-, released in response to lipopolysaccharide stimulation was significantly enhanced in the presence of UDP, and this effect was lost in the P2Y₆ KO macrophages. The endothelium-dependent relaxation of the aorta by UDP was abolished in KO P2Y₆ mice. The contractile effect of UDP on the aorta, observed when endothelial nitric-oxide synthase is blocked, was also abolished in P2Y₆-null mice. In conclusion, we generated P2Y₆-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.

Address correspondence to: Dr. Bernard Robaye, 10 rue A. Bolland, Gosselies 6041, Belgium. E-mail: brobaye{at}ulb.ac.be