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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:866.)
© 2000 American Heart Association, Inc.

Thrombosis

P2Y Receptor Regulation of PAI-1 Expression in Vascular Smooth Muscle Cells

Julie L. Bouchie; Hong-Chi Chen; Rebbeca Carney; J. Courtney Bagot; Peter A. Wilden; Edward P. Feener

From the Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Mass (J.L.B., H.-C.C., R.C., E.P.F.), and the Department of Pharmacology and Molecular Biology Program, University of Missouri, School of Medicine, Columbia, Mo (J.C.B., P.A.W.).

Correspondence to Edward P. Feener, PhD, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail edward.feener{at}joslin.harvard.edu

Abstract—P2Y-type purine and pyrimidine nucleotide receptors play important roles in the regulation of vascular hemostasis. In this article, the regulation of plasminogen activator inhibitor-1 (PAI-1) expression in rat aortic smooth muscle cells (RASMCs) by adenine and uridine nucleotides was examined and compared. Northern analysis revealed that RASMCs express multiple P2Y receptor subtypes, including P2Y₁, P2Y₂, and P2Y₆. Treatment of RASMCs with UTP increased PAI-1 mRNA expression and extracellular PAI-1 protein levels by 21-fold (P<0.001) and 7-fold (P<0.001), respectively. The ED₅₀ for the effect of UTP on PAI-1 expression was 1 µmol/L, and its maximal effect occurred at 3 hours. UDP stimulated a 5-fold increase (P<0.005) in PAI-1 expression. In contrast to these potent stimulatory effects of uridine nucleotides, ATP and 2-methylthioadenosine triphosphate (2-MeSATP) caused a small and transient increase in PAI-1 mRNA at 1 hour, followed by a rapid decrease to baseline levels. ADP produced only an inhibitory effect, reducing PAI-1 mRNA levels by 63% (P<0.05) at 3 hours. The relative nucleotide potency in stimulating PAI-1 expression is UTP>UDP>ATP=2-MeSATP, consistent with a predominant role of the P2Y₆ receptor. Further studies revealed that exposure of RASMCs to either ATP or ADP for 3 hours inhibited both UTP- and angiotensin II–stimulated PAI-1 expression by up to 90% (P<0.001). Thus, ATP induced a small and transient upregulation of PAI-1 that was followed by a strong inhibition of PAI-1 expression. These results show that extracellular adenine and uridine nucleotides exert potent and opposing effects on vascular PAI-1 expression.

Key Words: purinoceptors • nucleotides • plasminogen activator inhibitor • vascular smooth muscle cells • rats

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