Osteopontin-stimulated vascular smooth muscle cell migration is mediated by beta 3 integrin.
Osteopontin (OPN), a 41-kDa phosphorylated glycoprotein, has been detected in rat aorta and carotid arteries, and expression of its mRNA in blood vessels is strongly increased in response to vascular injury. To investigate the potential role of OPN in vascular pathophysiology, we studied the effect of rat OPN on aortic smooth muscle cell migration and proliferation in vitro. OPN enhanced the migration of rat smooth muscle cells in a time- and concentration-dependent manner with an EC50 value of 46 +/- 11 nmol/liter (n = 5). The maximal increase in cell migration by OPN was 29-fold over basal levels. OPN-induced smooth muscle cell migration was inhibited in a concentration-dependent manner by the monoclonal antibody F11, which recognizes the rat integrin subunit beta 3. In contrast, polyclonal antiserum recognizing the rat integrin beta 1 subunit did not inhibit smooth muscle cell migration in response to OPN, but did block fibronectin-promoted migration. Moreover, OPN-induced smooth muscle cell migration was dependent on the presence of extracellular divalent cations and was significantly inhibited by anti-OPN antibodies. OPN did not stimulate [3H]thymidine incorporation into cultured smooth muscle cells, indicating that it selectively enhanced migration. In view of the pathological significance of arterial smooth muscle cell migration in the formation of intimal thickening, our results suggest that smooth muscle cell recognition of OPN, probably through the vitronectin receptor, alpha v beta 3, could play a role in the cells' response to vascular injury and especially neointima formation.
Yue
T L
TL
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
McKenna
P J
PJ
Ohlstein
E H
EH
Farach-Carson
M C
MC
Butler
W T
WT
Johanson
K
K
McDevitt
P
P
Feuerstein
G Z
GZ
Stadel
J M
JM
D000818:Animals; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D039661:Integrin beta3; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009842:Oligopeptides; D053495:Osteopontin; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000276:immunology / Q000494:pharmacology*
D039661:Integrin beta3; D016023:Integrins; D009842:Oligopeptides; D010982:Platelet-Derived Growth Factor; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; C047981:arginyl-glycyl-aspartic acid