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1 Division of Experimental Vascular Research, Department of Medicine, University Hospital, SE-221 85 Lund, Sweden; Departments of 2 Pharmacology and 3 Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599; 4 Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710; 5 Inspire Pharmaceuticals Incorporated, Durham, North Carolina 27700; and Departments of 6 Oncology and 7 Cardiology, University Hospital, SE-221 85 Lund, Sweden
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) (UDP
S) was specific for
P2Y6 with no effect on P2Y1, P2Y2,
or P2Y4 receptors. UDPS 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 G2
phases. The intracellular signal pathways were dependent on
phospholipase C, possibly protein kinase C-
, and a tyrosine kinase
pathway but independent of Gi proteins, eicosanoids, and
protein kinase A. The half-life of P2Y6 receptor mRNA was
<1 h by competitive RT-PCR. The mitogen-activated protein kinase
kinase inhibitor PD-098059 significantly suppressed, whereas ATP and
interleukin-1 upregulated, expression of P2Y6 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.
uridine 5'-diphosphate; gene expression
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