Extracellular nucleotides induce arterial smooth muscle cell migration viaosteopontin

Migration and proliferation of arterial smooth muscle cells (SMCs) play a p rominent role in the development of atherosclerotic plaques and restenosis lesions. Most of the growth-regulatory molecules potentially involved in th ese pathological conditions also demonstrate chemotactic proper-ties. Extra cellular purine and pyrimidine nucleotides have been shown to induce cell c ycle progression and to elicit growth of cultured vascular SMCs. Moreover, the P2Y(2) ATP/UTP receptor was overexpressed in intimal thickening, sugges ting a role of these nucleotides in vascular remodeling. Using the Transwel l system migration assay, we demonstrate that extracellular ATP, UTP, and U DP exhibit a concentration-dependent chemotactic effect on cultured rat aor tic SMCs. UTP, the most powerful nucleotide inducer of migration, elicited significant responses from 10 nmol/L. In parallel. UTP increased osteoponti n expression dose-dependently. The blockade of osteopontin or its integrin receptors alpha,beta (3)/beta (5) by specific antibodies or antagonists inh ibited UTP-induced migration. Moreover, the blockade of ERK-1/ERK-2 MAP kin ase or rho protein pathways led to the inhibition of both UTP-induced osteo pontin increase and migration, demonstrating the central role of osteoponti n in this process. Taken together, these results suggest that extracellular nucleotides. and particularly UTP, can induce arterial SMC migration via t he action of osteopontin.