(Circulation. 1995;91:1107-1115.)
© 1995 American Heart Association, Inc.
Articles |
Role of Calcium/Calmodulin-Dependent Protein Kinase II in the Regulation of Vascular Smooth Muscle Cell Migration
From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md (R.R.P., C.B., S.J.S., R.M., E.G.L., M.T.C.), and the Department of Neurobiology and Anatomy, University of Texas Medical School, Houston (P.T.K.).
Correspondence to Michael T. Crow, PhD, Laboratory of Cardiovascular Science, Vascular Biology Group, NIH, National Institute on Aging, 4940 Eastern Ave, Baltimore, MD 21224.
Background The migration of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of many vascular diseases. We have previously shown that VSMC migration in response to platelet-derived growth factor (PDGF) is suppressed when cultured cells are growth-arrested and induced to differentiate. The present study was undertaken to elucidate the mechanism of this suppression.
Methods and Results While both proliferating and growth-arrested VSMCs upregulated expression of the immediate early response genes, c-fos and JE (monocyte chemoattractant protein 1), growth-arrested VSMCs exhibited much smaller changes in intracellular calcium in response to PDGF and failed to activate the calcium/calmodulin-dependent protein kinase II (CaM kinase II). Blocking calcium-calmodulin interactions (50 µmol/L W7) or the activation of CaM kinase II (10 µmol/L KN62) in proliferating cells blocked their migration by more than 90%, whereas inhibition of protein kinase C activation had no significant effect on migration. Pretreatment of growth-arrested VSMCs with the calcium ionophore ionomycin resulted in an approximately 2.5-fold activation of CaM kinase II and increased migration of growth-arrested cells to 84±6% that of proliferating cells. These effects of ionomycin were blocked by inhibitors of CaM kinase II. Constitutively activated (ie, calcium/calmodulin-independent) CaM kinase II introduced by gene transfection into growth-arrested cells significantly increased migration toward PDGF from <20% to >70% that of proliferating cells.
Conclusions These results demonstrate that activation of CaM kinase II is required for VSMC migration, that its activation in response to PDGF is suppressed in growth-arrested VSMCs, and that this suppression of CaM kinase II activation is responsible, in large part, for the failure of growth-arrested VSMCs to migrate toward PDGF.
Key Words: calcium • protein kinases • muscles, smooth • platelet-derived factors • cells
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