UDP acts as a growth factor for vascular smooth muscle cells by activation of P2Y6receptors

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Abstract
Mitogenic effects of the extracellular nucleotides ATP and UTP are mediated by P2Y1, P2Y2, and P2Y4 receptors. However, it has not been possible to examine the highly expressed UDP-sensitive P2Y6 receptor because of the lack of stable, selective agonists. In rat aorta smooth muscle cells (vascular smooth muscle cells; VSMC), UDP and UTP stimulated 3H-labeled thymidine incorporation with similar pEC50 values (5.96 and 5.69). Addition of hexokinase did not reduce the mitogenic effect of UDP. In cells transfected with P2Y receptors the stable pyrimidine agonist uridine 5'-O-(2-thiodiphosphate) (UDPβS) was specific for P2Y6 with no effect on P2Y1, P2Y2, or P2Y4 receptors. UDPβS stimulated [3H]thymidine and [3H]leucine incorporation and increased cell number in VSMC. Flow cytometry demonstrated that UDP stimulated cell cycle progression to both the S and G2phases. The intracellular signal pathways were dependent on phospholipase C, possibly protein kinase C-δ, and a tyrosine kinase pathway but independent of Gi proteins, eicosanoids, and protein kinase A. The half-life of P2Y6 receptor mRNA was 6 receptor mRNA. The results demonstrate that UDP stimulates mitogenesis through activation of P2Y6 receptors and that the receptor is regulated by factors important in the development of vascular disease.