Circulation Research. 2001;89:772-778
Published online before print September 13, 2001, doi: 10.1161/hh2101.098617
Published online before print September 13, 2001, doi: 10.1161/hh2101.098617
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Extracellular Nucleotides Induce Arterial Smooth Muscle Cell Migration Via Osteopontin
From INSERM U441, Pessac (H.C., C.D., M.-A.R., F.D., G.E., A.-P.G.); INSERM EPI9936, Faculté de Médecine Timone, Marseille (F.P.); and INSERM U533, Faculté des Sciences et Techniques, Nantes (G.L., P.P.), France.
Correspondence to Alain-Pierre Gadeau, INSERM U441, Avenue du Haut Lévêque, 33600 Pessac, France. E-mail alain.gadeau{at}bordeaux.inserm.fr
Migration and proliferation of arterial smooth muscle cells (SMCs) play a prominent role in the development of atherosclerotic plaques and restenosis lesions. Most of the growth-regulatory molecules potentially involved in these pathological conditions also demonstrate chemotactic properties. Extracellular purine and pyrimidine nucleotides have been shown to induce cell cycle progression and to elicit growth of cultured vascular SMCs. Moreover, the P2Y2 ATP/UTP receptor was overexpressed in intimal thickening, suggesting a role of these nucleotides in vascular remodeling. Using the Transwell system migration assay, we demonstrate that extracellular ATP, UTP, and UDP exhibit a concentration-dependent chemotactic effect on cultured rat aortic SMCs. UTP, the most powerful nucleotide inducer of migration, elicited significant responses from 10 nmol/L. In parallel, UTP increased osteopontin expression dose-dependently. The blockade of osteopontin or its integrin receptors 
vß3/ß5 by specific antibodies or antagonists inhibited UTP-induced migration. Moreover, the blockade of ERK-1/ERK-2 MAP kinase or rho protein pathways led to the inhibition of both UTP-induced osteopontin increase and migration, demonstrating the central role of osteopontin in this process. Taken together, these results suggest that extracellular nucleotides, and particularly UTP, can induce arterial SMC migration via the action of osteopontin.
Key Words: extracellular nucleotides • aortic smooth muscle cells • migration • osteopontin
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