Extracellular nucleotides induce arterial smooth muscle cell migration via osteopontin.
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 osteopontin.
Chaulet
H
H
INSERM U441, Pessac, France.
Desgranges
C
C
Renault
M A
MA
Dupuch
F
F
Ezan
G
G
Peiretti
F
F
Loirand
G
G
Pacaud
P
P
Gadeau
A P
AP
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D015194:Diffusion Chambers, Culture; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009711:Nucleotides / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D053495:Osteopontin; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012795:Sialoglycoproteins / Q000378:metabolism*; D014530:Uridine Diphosphate / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009711:Nucleotides; D009842:Oligopeptides; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C092614:glycyl-arginyl-glycyl-glutamyl-serine; D053495:Osteopontin; D014530:Uridine Diphosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C049554:glycyl-arginyl-glycyl-aspartyl-serine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; D002118:Calcium; D014544:Uridine Triphosphate