ROCK controls matrix synthesis in vascular smooth muscle cells - Coupling vasoconstriction to vascular remodeling

被引:63
作者
Chapados, Rene
Abe, Khotaro
Ihida-Stansbury, Kaori
McKean, David
Gates, Adam T.
Kern, Michael
Merklinger, Sandra
Elliott, John
Plant, Anne
Shimokawa, Hiroaki
Jones, Peter Lloyd
机构
[1] Univ Penn, Sch Med, Inst Med & Engn, Vagelos Res Labs 1010, Philadelphia, PA 19104 USA
[2] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
[3] Kyushu Univ, Grad Sch Med Sci, Fukuoka 812, Japan
[4] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[5] Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA
[6] Med Univ S Carolina, Dept Anat, Charleston, SC 29425 USA
[7] Hosp Sick Children, Toronto, ON M5G 1X8, Canada
[8] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA
关键词
tenascin-C; smooth muscle; ROCK; pulmonary hypertension;
D O I
10.1161/01.RES.0000246172.77441.f1
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:837 / 844
页数:8
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