title: ROCK controls matrix synthesis in vascular smooth muscle cells: coupling vasoconstriction to vascular remodeling.
abstract: 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.
authors.affiliation: Children's Hospital of Philadelphia, PA, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Chapados
authors.forename: Khotaro
authors.initials: K
authors.lastname: Abe
authors.forename: Kaori
authors.initials: K
authors.lastname: Ihida-Stansbury
authors.forename: David
authors.initials: D
authors.lastname: McKean
authors.forename: Adam T
authors.initials: AT
authors.lastname: Gates
authors.forename: Michael
authors.initials: M
authors.lastname: Kern
authors.forename: Sandra
authors.initials: S
authors.lastname: Merklinger
authors.forename: John
authors.initials: J
authors.lastname: Elliott
authors.forename: Anne
authors.initials: A
authors.lastname: Plant
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Peter Lloyd
authors.initials: PL
authors.lastname: Jones
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000199:Actins / Q000502:physiology; D000818:Animals; D001808:Blood Vessels / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D048430:Cell Shape / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology / Q000648:ultrastructure; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D013314:Stress, Mechanical; D019063:Tenascin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D000199:Actins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D019063:Tenascin; D016686:Monocrotaline; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein; C049347:fasudil