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First published online 11 April 2006
doi: 10.1242/jcs.02805

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Agonist- and depolarization-induced signals for myosin light chain phosphorylation and force generation of cultured vascular smooth muscle cells

¹ Boston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472, USA
² Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

^* Author for correspondence (e-mail: Kitazawa{at}bbri.org)

Accepted 19 January 2006

Phosphorylation of myosin light chain (MLC) and contraction of differentiated smooth muscle cells in vascular walls are regulated by Ca²⁺-dependent activation of MLC kinase, and by Rho-kinase- or protein-kinases-C-dependent inhibition of MLC phosphatase (MLCP). We examined regulatory pathways for MLC kinase and MLCP in cultured vascular smooth muscle cells (VSMCs), and for isometric force generation of VSMCs reconstituted in collagen fibers. Protein levels of RhoA, Rho-kinase and MYPT1 (a regulatory subunit of MLCP) were upregulated in cultured VSMCs, whereas a MLCP inhibitor protein, CPI-17, was downregulated. Endothelin-1 evoked a steady rise in levels of Ca²⁺, MLC phosphorylation and the contractile force of VSMCs, whereas angiotensin-II induced transient signals. Also, Thr853 phosphorylation of MYPT1 occurred in response to stimuli, but neither agonist induced phosphorylation of MYPT1 at Thr696. Unlike fresh aortic tissues, removal of Ca²⁺ or addition of voltage-dependent Ca²⁺-channel blocker did not inhibit contractions of reconstituted VSMC fibers induced by agonists or even high concentrations of extracellular K⁺ ions. Inhibitors of Ins(1,4,5)P₃-receptor and Rho-kinase antagonized agonist-induced or high-K⁺-induced contraction in both reconstituted fibers and fresh tissues. These results indicate that both Ins(1,4,5)P₃-induced Ca²⁺ release and Rho-kinase-induced MYPT1 phosphorylation at Thr853 play pivotal roles in MLC phosphorylation of cultured VSMCs where either Ca²⁺-influx or CPI-17-MLCP signaling is downregulated.

Key words: Calcium channel, Inositol 1,4,5-trisphosphate receptor, RhoA, CPI-17, Vascular smooth muscle, Arteriosclerosis

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