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(Circulation Research. 2006;99:837.)
© 2006 American Heart Association, Inc.

Molecular Medicine

ROCK Controls Matrix Synthesis in Vascular Smooth Muscle Cells

Coupling Vasoconstriction to Vascular Remodeling

Rene Chapados, Khotaro Abe, Kaori Ihida-Stansbury, David McKean, Adam T. Gates, Michael Kern, Sandra Merklinger, John Elliott, Anne Plant, Hiroaki Shimokawa, Peter Lloyd Jones

From the Children’s Hospital of Philadelphia (R.C., A.T.G.), Pa; Kyushu University Graduate School of Medical Sciences (K.A., H.S.), Fukuoka, Japan; The Institute for Medicine and Engineering (K.I.-S., P.L.J.) and the Department of Pathology and Laboratory Medicine (P.L.J.), University of Pennsylvania, Philadelphia; Department of Pediatrics (D.M.), University of Colorado Health Sciences Center, Denver; Department of Anatomy (M.K.), Medical University of South Carolina, Charleston; The Hospital for Sick Children (S.M.), Toronto, Ontario, Canada; and National Institute of Standards and Technology (J.E., A.P.), Gaithersburg, Md.

Correspondence to Peter Lloyd Jones, PhD, University of Pennsylvania School of Medicine, Institute for Medicine & Engineering, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, PA 19104-6383. E-mail jonespl{at}mail.med.upenn.edu

Tenascin-C (TN-C) is an extracellular matrix (ECM) protein expressed within remodeling systemic and pulmonary arteries (PAs), where it supports vascular smooth muscle cell (SMC) proliferation. Previously, we showed that A10 SMCs cultivated on native type I collagen possess a spindle-shaped morphology and do not express TN-C, whereas those on denatured collagen possess a well-defined F-actin stress fiber network, a spread morphology, and they do express TN-C. To determine whether changes in cytoskeletal architecture control TN-C, SMCs on denatured collagen were treated with cytochalasin D, which decreased SMC spreading and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling effectors required for TN-C transcription. Next, to determine whether cell shape, dictated by the F-actin cytoskeleton, regulates TN-C, different geometries of SMCs (ranging from spread to round) were engineered on denatured collagen: as SMCs progressively rounded, ERK1/2 activity and TN-C transcription declined. Because RhoA and Rho kinase (ROCK) regulate cell morphology by controlling cytoskeletal architecture, we reasoned that these factors might also regulate TN-C. Indeed, SMCs on denatured collagen possessed higher levels of RhoA activity than those on native collagen, and blocking RhoA or ROCK activities attenuated SMC spreading, ERK1/2 activity, and TN-C expression in SMCs on denatured collagen. Thus, ROCK controls the configuration of the F-actin cytoskeleton and SMC shape in a manner that is permissive for ERK1/2-dependent production of TN-C. Finally, we showed that inhibition of ROCK activity suppresses SMC TN-C expression and disease progression in hypertensive rat PAs. Thus, in addition to its role in regulating vasoconstriction, ROCK also controls matrix production.

Key Words: tenascin-C • smooth muscle • ROCK • pulmonary hypertension

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