Extracellular nucleotides induce arterial smooth muscle cell migration via osteopontin.
Circulation Research. 2001-10-26; 89(9): 772-778
Lire sur PubMed
Chaulet H(1), Desgranges C, Renault MA, Dupuch F, Ezan G, Peiretti F, Loirand G, Pacaud P, Gadeau AP.
(1)INSERM U441, Pessac, France.
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 P2Y(2)
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
alpha(v)beta(3)/beta(5) 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