(Hypertension. 1999;33:183-189.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
TNF-
–Induced Migration of Vascular Smooth Muscle Cells Is MAPK Dependent
From the Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, School of Medicine (S.G., Y.K., H.K., W.A.H., R.L.); and the Department of Medicine/Cardiology, Virchow Klinikum, Humboldt University Berlin and German Heart Institute, Berlin, Germany (S.G., E.F.).
Correspondence to Ronald E. Law, PhD, UCLA School of Medicine, Division of Endocrinology, Diabetes and Hypertension, Warren Hall, Second Floor, Suite 24-130, 900 Veteran Ave, Box 957073, Los Angeles, CA 90095. E-mail rlaw{at}med1.medsch.ucla.edu
Abstract—Migration of vascular
smooth muscle cells (VSMC) is a key event in neointimal
formation and atherosclerosis that may be linked to the
accumulation of inflammatory cells and release of chemotactic
cytokines. Tumor necrosis factor-
(TNF-) induces
chemotaxis of inflammatory cells and fibroblasts, but little is known
about chemotactic signaling by TNF- in VSMC. The aim of this study
was to investigate the role of TNF- in VSMC migration and to
elucidate the chemotactic signaling pathways mediating this action.
TNF- (50 to 400 U/mL) induced migration of cultured rat aortic VSMC
in a dose-dependent manner. Because activation of the extracellular
signal-regulated kinase 1/2 mitogen-activated protein kinase
(MAPK) is known to be required in platelet-derived growth
factor–directed and angiotensin II–directed migration of
these cells, we used the MAPK-inhibitor PD98059 to
determine if chemotactic signaling by TNF- involves the MAPK pathway
as well. We found that TNF-–directed migration was substantially
inhibited by PD98059. TNF- (100 U/mL) transiently activated
MAPK with a maximal induction 10 minutes after stimulation that
returned to baseline levels by 2 hours after treatment. Only a single
peak of increased MAPK activity was seen. PD98059 also blocked
TNF-–stimulated MAPK activation in a concentration-dependent
manner, which is consistent with its inhibition of
TNF-–directed migration. To identify which TNF- receptor is
involved in TNF-–induced MAPK activation, antibodies against the
p55 TNF- receptor-1 (TNF-R1) and the p75 TNF- receptor-2 (TNF-R2)
were used. VSMC express both receptors, but TNF-–induced MAPK
activation was inhibited only by the TNF-R1 antibody. The TNF-R2
antibody had no effect. Thiazolidinediones are known to inhibit TNF-
signaling in adipose tissue and attenuate platelet-derived growth
factor–directed and angiotensin II–directed migration in
VSMC. We therefore investigated the effects of the thiazolidinediones
troglitazone (TRO) and rosiglitazone (RSG) on TNF-–induced
migration. Both TRO and RSG inhibited migration, but neither attenuated
TNF-–induced MAPK activation, indicating that their antimigration
activity was exerted downstream of MAPK. These experiments provide the
first evidence that early activation of MAPK is a crucial event in
TNF-–mediated signal transduction leading to VSMC migration.
Moreover, inhibition of TNF-–directed migration by the insulin
sensitizers TRO and RSG underscores their potential as
vasculoprotective agents.
Key Words: signal transduction • muscle, smooth • atherosclerosis • MAPK • cytokine • migration
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