Functional P2Y2 nucleotide receptors mediate uridine 5′-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries

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

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

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 (Cam) in response to P2Y receptor agonists. In contrast to UDP, activation by UTP or adenosine 5′-triphosphate (ATP) greatly increased Cam, 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.

Original languageEnglish (US)
Pages (from-to)2720-2726
Number of pages7
JournalCirculation
Volume106
Issue number21
DOIs
StatePublished - Nov 19 2002
Externally publishedYes

Fingerprint

Purinergic P2Y2 Receptors
Tunica Intima
Uridine Triphosphate
Carotid Arteries
Hyperplasia
Nucleotides
Rabbits
Smooth Muscle Myocytes
Osteopontin
Adenosine Triphosphate
Up-Regulation
Neointima
Messenger RNA
Uridine Diphosphate
Fura-2
Antisense Oligonucleotides
Vascular System Injuries
Silicones
G-Protein-Coupled Receptors
Aorta

Keywords

  • Calcium
  • Carotid arteries
  • Nucleotide
  • Receptors
  • Restenosis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Functional P2Y2 nucleotide receptors mediate uridine 5′-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. / Seye, Cheikh; Kong, Qiongman; Erb, Laurie; Garrad, Richard C.; Krugh, Brent; Wang, Meifang; Turner, John T.; Sturek, Michael; González, Fernando A.; Weisman, Gary A.

In: Circulation, Vol. 106, No. 21, 19.11.2002, p. 2720-2726.

Research output: Contribution to journalArticle

Seye, Cheikh ; Kong, Qiongman ; Erb, Laurie ; Garrad, Richard C. ; Krugh, Brent ; Wang, Meifang ; Turner, John T. ; Sturek, Michael ; González, Fernando A. ; Weisman, Gary A. / Functional P2Y2 nucleotide receptors mediate uridine 5′-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. In: Circulation. 2002 ; Vol. 106, No. 21. pp. 2720-2726.
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T1 - Functional P2Y2 nucleotide receptors mediate uridine 5′-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries

AU - Seye, Cheikh

AU - Kong, Qiongman

AU - Erb, Laurie

AU - Garrad, Richard C.

AU - Krugh, Brent

AU - Wang, Meifang

AU - Turner, John T.

AU - Sturek, Michael

AU - González, Fernando A.

AU - Weisman, Gary A.

PY - 2002/11/19

Y1 - 2002/11/19

N2 - 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 (Cam) in response to P2Y receptor agonists. In contrast to UDP, activation by UTP or adenosine 5′-triphosphate (ATP) greatly increased Cam, 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.

AB - 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 (Cam) in response to P2Y receptor agonists. In contrast to UDP, activation by UTP or adenosine 5′-triphosphate (ATP) greatly increased Cam, 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.

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KW - Nucleotide

KW - Receptors

KW - Restenosis

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