Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Research Paper

Signal Transduction in Matrix Contraction and the Migration of Vascular Smooth Muscle Cells in Three-Dimensional Matrix

Li S.a · Moon J.J.a · Miao H.b · Jin G.b · Chen B.P.C.b · Yuan S.b · Hu Y.b · Usami S.b · Chien S.b

Author affiliations

aDepartment of Bioengineering, University of California, Berkeley, Calif., and bDepartment of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, Calif., USA

Related Articles for ""

J Vasc Res 2003;40:378–388

Do you have an account?

Login Information





Contact Information










I have read the Karger Terms and Conditions and agree.



Login Information





Contact Information










I have read the Karger Terms and Conditions and agree.



To view the fulltext, please log in

To view the pdf, please log in

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.


Save over 20% compared to the individual article price.
Learn more

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restrictions apply

Rental: USD 8.50
Cloud: USD 20.00


Select

Subscribe

  • Access to all articles of the subscribed year(s) guaranteed for 5 years
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates


Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview
Abstract of Research Paper

Received: January 24, 2003
Accepted: April 23, 2003
Published online: September 26, 2003
Issue release date: July – August

Number of Print Pages: 11
Number of Figures: 8
Number of Tables: 0

ISSN: 1018-1172 (Print)
eISSN: 1423-0135 (Online)

For additional information: https://www.karger.com/JVR

Abstract

The interaction of vascular smooth muscle cells (SMCs) and extracellular matrix plays important roles in vascular remodeling. We investigated the signaling pathways involved in SMC-induced matrix contraction and SMC migration in three-dimensional (3D) collagen matrix. Matrix contraction is inhibited by the disruption of actin filaments but not microtubules. Therefore, we investigated the roles of signaling pathways related to actin filaments in matrix contraction. SMC-induced matrix contraction was markedly blocked (–80%) by inhibiting the Rho-p160ROCK pathway and myosin light chain kinase, and was decreased to a lesser extent (30–40%) by a negative mutant of Rac and inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase) or p38 mitogen-activated protein kinase (MAPK), but it was not affected by the inhibition of Ras and Cdc42-Wiskott-Aldrich syndrome protein (WASP) pathways. Inhibition of extracellular-signal-regulated kinase (ERK) decreased SMC-induced matrix contraction by only 15%. The migration speed and persistence of SMCs in the 3D matrix were decreased by the inhibition of p160ROCK, PI 3-kinase, p38 MAPK or WASP to different extents, and p160ROCK inhibitor had the strongest inhibitory effect. Our results suggest that the SMC-induced matrix contraction and the migration of SMCs in 3D matrix share some signaling pathways leading to force generation at cell-matrix adhesions and that various signaling pathways have different relative importance in the regulations of these processes in SMCs.

© 2003 S. Karger AG, Basel


References

  1. Owens GK: Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 1995;75:487–517.
  2. Thyberg J: Differentiated properties and proliferation of arterial smooth muscle cells in culture. Int Rev Cytol 1996;169:183–265.
  3. Bauters C, Isner JM: The biology of restenosis. Prog Cardiovasc Dis 1997;40:107–116.
  4. Libby P, Tanaka H: The molecular bases of restenosis. Prog Cardiovasc Dis 1997;40:97–106.
  5. Weinberg CB, Bell E: A blood vessel model constructed from collagen and cultured vascular cells. Science 1986;231:397–400.
  6. Seliktar D, Black RA, Vito RP, Nerem RM: Dynamic mechanical conditioning of collagen-gel blood vessel constructs induces remodeling in vitro. Ann Biomed Eng 2000;28:351–362.
  7. Li S, Lao J, Chen BP, Li YS, Zhao Y, Chu J, Chen KD, Tsou TC, Peck K, Chien S: Genomic analysis of smooth muscle cells in 3-dimensional collagen matrix. FASEB J 2003;17:97–99.
  8. Lee RT, Berditchevski F, Cheng GC, Hemler ME: Integrin-mediated collagen matrix reorganization by cultured human vascular smooth muscle cells. Circ Res 1995;76:209–214.
  9. Gotwals PJ, Chirosso G, Lindner V, Yang JL, Ling L, Fawell SE, Koteliansky VE: The 9111 integrin is expressed during neointima formation in rat arteries and mediates collagen matrix reorganization. J Clin Invest 1996;97:2469–2477.
  10. Pickering JG, Chow LH, Li SH, Rogers KA, Rocnik EF, Zhong R, Chan BMC: 1551 integrin expression and luminal edge fibronectin matrix assembly by smooth muscle cells after arterial injury. Am J Pathol 2000;156:453–465.
  11. Ridley AJ, Hall A: The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 1992;70:389–399.
  12. Hotchin NA, Hall A: The assembly of integrin adhesion complexes requires both extracellular matrix and intracellular rho/rac GTPases. J Cell Biol 1995;131:1857–1865.
  13. Van Aelst L, D’Souza-Schorey C: Rho GTPases and signaling networks. Genes Dev 1997;11:2295–2322.
  14. Ridley AJ: Rho GTPases and cell migration. J Cell Sci 2001;114:2713–2722.
  15. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K: Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996;273:245–248.
  16. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S: Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 1997;389:990–994.
  17. Fukata Y, Amano M, Kaibuchi K: Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 2001;22:32–39.
    External Resources
  18. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A: The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 1992;70:401–410.
  19. Rottner K, Hall A, Small JV: Interplay between Rac and Rho in the control of substrate contact dynamics. Curr Biol 1999;9:640–648.
  20. Small JV, Rottner K, Kaverina I: Functional design in the actin cytoskeleton. Curr Opin Cell Biol 1999;11:54–60.
  21. Nobes CD, Hall A: Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 1995;81:53–62.
  22. Kozma R, Ahmed S, Best A, Lim L: The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol Cell Biol 1995;15:1942–1952.
  23. Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D: Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 1998;279:558–560.
  24. Keely PJ, Westwick JK, Whitehead IP, Der CJ, Parise LV: Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 1997;390:632–636.
  25. Higgs HN, Pollard TD: Regulation of actin filament network formation through ARP2/3 complex: Activation by a diverse array of proteins. Annu Rev Biochem 2001;70:649–676.
  26. Miki H, Sasaki T, Takai Y, Takenawa T: Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP. Nature 1998;391:93–96.
  27. Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner MW: The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 1999;97:221–231.
  28. Katz ME, McCormick F: Signal transduction from multiple Ras effectors. Curr Opin Genet Dev 1997;7:75–79.
  29. Joneson T, Bar-Sagi D: Ras effectors and their role in mitogenesis and oncogenesis. J Mol Med 1997;75:587–593.
  30. Olson MF, Marais R: Ras protein signalling. Semin Immunol 2000;12:63–73.
  31. Indolfi C, Avvedimento EV, Rapacciuolo A, Dilorenzo E, Esposito G, Stabile E, Feliciello A, Mele E, Giuliano P, Condorelli G, Chiariello M: Inhibition of cellular Ras prevents smooth muscle cell proliferation after vascular injury in vivo. Nat Med 1995;1:541–545.
  32. Jin G, Chieh-Hsi J, Li YS, Hu YL, Shyy JYJ, Chien S: Effects of active and negative mutants of Ras on rat arterial neointima formation. J Surg Res 2000;94:124–132.
  33. Wu CH, Lin CS, Hung JS, Wu CJ, Lo PH, Jin G, Shyy YJ, Mao SJ, Chien S: Inhibition of neointimal formation in porcine coronary artery by a Ras mutant. J Surg Res 2001;99:100–106.
  34. Robinson MJ, Cobb MH: Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 1997;9:180–186.
  35. Garrington TP, Johnson GL: Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 1999;11:211–218.
  36. Schaeffer HJ, Weber MJ: Mitogen-activated protein kinases: Specific messages from ubiquitous messengers. Mol Cell Biol 1999;19:2435–2444.
  37. Cheresh DA, Leng J, Klemke RL: Regulation of cell contraction and membrane ruffling by distinct signals in migratory cells. J Cell Biol 1999;146:1107–1116.
  38. Minden A, Lin A, Claret FX, Abo A, Karin M: Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 1995;81:1147–1157.
  39. Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS: The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 1995;81:1137–1146.
  40. Zhang SJ, Han JH, Sells MA, Chernoff J, Knaus UG, Ulevitch RJ, Bokoch GM: Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem 1995;270:23934–23936.
  41. Huot J, Houle F, Marceau F, Landry J: Oxidative stress-induced actin reorganization mediated by the p38 mitogen-activated protein kinase/heat shock protein 27 pathway in vascular endothelial cells. Circ Res 1997;80:383–392.
  42. Kreisberg JI, Ghosh-Choudhury N, Radnik RA, Schwartz MA: Role of Rho and myosin phosphorylation in actin stress fiber assembly in mesangial cells. Am J Physiol 1997;273:F283–F288.
  43. Kjoller L, Hall A: Signaling to Rho GTPases. Exp Cell Res 1999;253:166–179.
  44. Bishop AL, Hall A: Rho GTPases and their effector proteins. Biochem J 2000;348:241–255.
  45. Ganitkevich V, Hasse V, Pfitzer G: Ca2+-dependent and Ca2+-independent regulation of smooth muscle contraction. J Muscle Res Cell Motil 2002;23:47–52.
  46. Ueno H, Yamamoto H, Ito SI, Li JJ, Takeshita A: Adenovirus-mediated transfer of a dominant-negative H-ras suppresses neointimal formation in balloon-injured arteries in vivo. Arterioscler Thromb Vasc Biol 1997;17:898–904.
  47. Qiu RG, Chen J, Kirn D, McCormick F, Symons M: An essential role for Rac in Ras transformation. Nature 1995;374:457–459.
  48. Joneson T, White MA, Wigler MH, Barsagi D: Stimulation of membrane ruffling and Map kinase activation by distinct effectors of Ras. Science 1996;271:810–812.
  49. Kotani K, Yonezawa K, Hara K, Ueda H, Kitamura Y, Sakaue H, Ando A, Chavanieu A, Calas B, Grigorescu F, Nishiyama M, Waterfield MD, Kasuga M: Involvement of phosphoinositide 3-kinase in insulin- or IGF-1-induced membrane ruffling. EMBO J 1994;13:2313–2321.
  50. Hawkins PT, Eguinoa A, Qiu RG, Stokoe D, Cooke FT, Walters R, Wennstrom S, Claesson-Welsh L, Evans T, Symons M, Stephens L: PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase. Curr Biol 1995;5:393–403.
  51. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J: Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 1997;89:457–467.
  52. Schmitz AA, Govek EE, Bottner B, Van Aelst L: Rho GTPases: Signaling, migration, and invasion. Exp Cell Res 2000;261:1–12.
    External Resources
  53. Evers EE, Zondag GC, Malliri A, Price LS, ten Klooster JP, van der Kammen RA, Collard JG: Rho family proteins in cell adhesion and cell migration. Eur J Cancer 2000;36:1269–1274.
  54. Li C, Cantor WJ, Nili N, Robinson R, Fenkell L, Tran YL, Whittingham HA, Tsui W, Cheema AN, Sparkes JD, Pritzker K, Levy DE, Strauss BH: Arterial repair after stenting and the effects of GM6001, a matrix metalloproteinase inhibitor. J Am Coll Cardiol 2002;39:1852–1858.
  55. Nobes CD, Hall A: Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 1999;144:1235–1244.
  56. Sawada N, Itoh H, Ueyama K, Yamashita J, Doi K, Chun TH, Inoue M, Masatsugu K, Saito T, Fukunaga Y, Sakaguchi S, Arai H, Ohno N, Komeda M, Nakao K: Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation 2000;101:2030–2033.
  57. McDonald JA, Quade BJ, Broekelmann TJ, LaChance R, Forsman K, Hasegawa E, Akiyama S: Fibronectin’s cell-adhesive domain and an amino-terminal matrix assembly domain participate in its assembly into fibroblast pericellular matrix. J Biol Chem 1987;262:2957–2967.
  58. Akiyama SK, Yamada SS, Chen WT, Yamada KM: Analysis of fibronectin receptor function with monoclonal antibodies: Roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J Cell Biol 1989;109:863–875.
  59. Zhong CL, Chrzanowska-Wodnicka M, Brown J, Shaub A, Belkin AM, Burridge K: Rho-mediated contractility exposes a cryptic site in fibronectin and induces fibronectin matrix assembly. J Cell Biol 1998;141:539–551.
  60. Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P: Inhibition of myosin light chain kinase by p21-activated kinase. Science 1999;283:2083–2085.
  61. Kozma R, Sarner S, Ahmed S, Lim L: Rho family GTPases and neuronal growth cone remodelling: Relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol Cell Biol 1997;17:1201–1211.
  62. van Leeuwen FN, Kain HET, van der Kammen RA, Michiels F, Kranenburg OW, Collard JG: The guanine nucleotide exchange factor Tiam1 affects neuronal morphology: Opposing roles for the small GTPases Rac and Rho. J Cell Biol 1997;139:797–807.
  63. Sheridan CM, Occleston NL, Hiscott P, Kon CH, Khaw PT, Grierson I: Matrix metalloproteinases: A role in the contraction of vitreo-retinal scar tissue. Am J Pathol 2001;159:1555–1566.
  64. Davis GE, Pintar Allen KA, Salazar R, Maxwell SA: Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. J Cell Sci 2001;114:917–930.
  65. Deryugina EI, Bourdon MA, Reisfeld RA, Strongin A: Remodeling of collagen matrix by human tumor cells requires activation and cell surface association of matrix metalloproteinase-2. Cancer Res 1998;58:3743–3750.
  66. Zempo N, Kenagy RD, Au YP, Bendeck M, Clowes MM, Reidy MA, Clowes AW: Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery. J Vasc Surg 1994;20:209–217.

Article / Publication Details

First-Page Preview
Abstract of Research Paper

Received: January 24, 2003
Accepted: April 23, 2003
Published online: September 26, 2003
Issue release date: July – August

Number of Print Pages: 11
Number of Figures: 8
Number of Tables: 0

ISSN: 1018-1172 (Print)
eISSN: 1423-0135 (Online)

For additional information: https://www.karger.com/JVR


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.