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(Circulation. 2002;106:2720.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Functional P2Y₂ Nucleotide Receptors Mediate Uridine 5'-Triphosphate–Induced Intimal Hyperplasia in Collared Rabbit Carotid Arteries

Cheikh I. Seye, PhD; Qiongman Kong, BS; Laurie Erb, PhD; Richard C. Garrad, PhD; Brent Krugh, MS; Meifang Wang, MS; John T. Turner, PhD; Michael Sturek, PhD; Fernando A. González, PhD; Gary A. Weisman, PhD

From Departments of Biochemistry (C.I.S., Q.K., L.E., B.K., G.A.W.), Pharmacology (J.T.T.), Physiology (M.W., M.S.), and Internal Medicine (M.W., M.S.), University of Missouri-Columbia, Columbia, Mo; Biomedical Sciences Department (R.C.G.), Southwest Missouri State University, Springfield, Mo; and Department of Chemistry (F.A.G.), University of Puerto Rico, Río Piedras, Puerto Rico.

Correspondence to Cheikh Seye, PhD, Department of Biochemistry, M121 Medical Sciences Bldg, University of Missouri-Columbia, Columbia, MO 65212. E-mail seyec{at}missouri.edu

Background— Extracellular uridine 5'-triphosphate (UTP) induces mitogenic activation of smooth muscle cells (SMCs) through binding to P2Y₂ nucleotide receptors. P2Y₂ receptor mRNA is upregulated in intimal lesions of rat aorta, but it is unclear how this G-protein–coupled receptor contributes to development of intimal hyperplasia.

Methods and Results— This study used a silicone collar placed around rabbit carotid arteries to induce vascular injury and intimal thickening. Collar placement caused rapid upregulation of P2Y₂ receptor mRNA in medial SMCs before appearance of neointima. Fura-2 digital imaging of single SMCs was used to measure changes in myoplasmic calcium concentration (Ca_m) in response to P2Y receptor agonists. In contrast to UDP, activation by UTP or adenosine 5'-triphosphate (ATP) greatly increased Ca_m, which indicates upregulation of functional P2Y₂ receptors at which UTP and ATP are equipotent agonists. The number of responsive cells was significantly greater for freshly dispersed SMCs from collared arteries than for controls. Perivascular infusion of UTP (100 µmol/L) within the collar significantly enhanced neointimal development. Intimas that resulted from UTP exposure were infiltrated by macrophages. Moreover, increased expression of osteopontin occurred in response to in situ application of UTP. ATP or UTP also stimulated osteopontin expression in cultured SMCs in a dose-dependent manner. Furthermore, P2Y₂ antisense oligonucleotide inhibited osteopontin expression induced by UTP.

Conclusions— These findings indicate for the first time a role for the UTP/ATP receptor, P2Y₂, in development of intimal hyperplasia associated with atherosclerosis and restenosis.

Key Words: nucleotide • carotid arteries • receptors • restenosis • calcium

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