Abstract
Mechanical forces play important roles in development and disease of most tissues. In vivo studies have illustrated that increased mechanical load as seen during neonatal development or in the hypertensive adult promote a fibrotic response in the heart. In vitro studies have established that mechanical stretch of isolated cardiac fibroblasts directly stimulates expression of extracellular matrix components and proliferation, both hallmarks of fibrosis. While significant advances have been made in understanding the effects of mechanical forces on cardiac fibroblasts, many questions remain regarding the mechanisms whereby mechanical forces are transduced into changes in cellular phenotype. The linkage between the extracellular matrix, integrin receptors and the cytoskeleton undoubtedly plays a critical role in this process. We have recently shown that mechanical stretch induces rapid changes in cardiac fibroblast morphology and the organization of the actin cytoskeleton. The Rho family of small GTPases has received considerable attention in their role in organizing the actin cytoskeleton. Data is presented herein providing quantitative analysis of alterations in the activation and subcellular organization of the small GTPase Rac-1 following equibiaxial stretch of isolated cardiac fibroblasts.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abe M, Ho C-H, Kamm KE, Grinnell F (2003) Different molecular motors mediate platlet-derived growth factor and lysophosphatidic acid-stimulated floating collagen matrix contraction. J Biol Chem 278: 47707–47712.
Aikawa R, Nagai T, Tanaka M, Zou Y, Ishihara T, Takano H, Hasegawa H, Akazawa H, Mizukami M, Nagai R, Komuro I (2001) Reactive oxygen species in mechanical stress-induced cardiac hypertrophy. Biochem Biophys Res Commun 289: 901–907.
Anderson JC, Babb AL, Hlastala MP (2005) A fractal analysis of the radial distribution of bronchial capillaries around large airways. J Appl Physiol 98: 850–855.
Atance J, Yost MJ, Carver W (2004) Influences of the extracellular matrix on the regulation of cardiac fibroblast behavior by mechanical stretch. J Cell Physiol 200: 377–386.
Baish JW, Jain RK (2000) Fractals and cancer. Cancer Res 60: 3683–3688.
Bassett CAL, Hermann L (1961) Influence of oxygen concentration and mechanical factors on differentiation of connective tissue in vitro. Nature 193: 460–461.
Behar TN (2001) Analysis of fractal dimension of O2A glial cells differentiating in vitro. Methods 24: 331–339.
Bernard F, Bossu JL, Gaillard S (2001) Identification of living oligodendrocyte developmental stages by fractal analysis of cell morphology. J Neurosci Res 65: 439–445.
Bershadsky A, Kozlov M, Geiger B (2006) Adhesion-mediated mechanosensitivity: a time to experiment, and a time to theorize. Curr Opin Cell Biol 18: 472–481.
Borg TK, Caulfield JB (1981) The collagen matrix of the heart. Fed Proc 40: 2037–2041.
Borg TK, Rubin K, Lundgren E, Borg K, Obrink B (1984) Recognition of extracellular matrix components by neonatal and adult cardiac myocytes. Dev Biol 104: 86–96.
Borodinsky LN, Fiszman ML (2001) A single-cell model to study changes in neuronal fractal dimension. Methods 24: 341–345.
Brown JH, Del Re DP, Sussman MA (2006) The Rac and Rho hall of fame: a decade of hypertrophic signaling hits. Circ Res 98: 730–742.
Butt RP, Laurent GJ, Bishop JE (1995) Collagen production and replication by cardiac fibroblasts is enhanced in response to diverse classes of growth factors. Eur J Cell Biol 68: 330–335.
Caldwell CB, Moran EL, Bogoch ER (1998) Fractal dimension as a measure of altered trabecular bone in experimental inflammatory arthritis. J Bone Miner Res 13: 978–985.
Camelliti P, Borg TK, Kohl P (2005) Structural and functional characterization of cardiac fibroblasts. Cardiovasc Res 65: 40–51.
Carver W, Nagpal ML, Nachtigal M, Borg TK, Terracio L (1991) Collagen expression in mechanically stimulated cardiac fibroblasts. Circ Res 69: 116–122.
Carver W, Terracio L. Borg TK (1993) Expression and accumulation of interstitial collagen in the neonatal rat heart. Anat Rec 511–520.
Caserta F, Eldred WD, Fernandez E, Hausman RE, Stanford LR, Bulderev SV, Schwarzer S, Stanley HE (1995) Determination of fractal dimension of physiologically characterized neurons in two and three dimensions. J Neurosci Methods 56: 133–144.
Catalucci D, Latronico MV, Ellingsen O, Condorelli G (2008) Physiological myocardial hypertrophy: how and why? Front Biosci 13: 312–324.
Cross SS (1997) Fractals in pathology. J Pathol 182: 1–8.
DeMeester SL, Cobb JP, Hotchkiss RS, Osborne DF, Karl IE, Tinsley KW, Buchman TG (1998). Stress-induced fractal rearrangement of the endothelial cell cytoskeleton causes apoptosis. Surgery 124: 362–371.
Fuseler JW, Merrill DM, Rogers JA, Grisham MB, Wolf RE (2006) Analysis and quantitation of NF-kappa B nuclear translocation in tumor necrosis factor alpha (TNF-alpha) activated vascular endothelial cells. Microsc Microanal 12: 269–276
Fuseler JW, Millette CF, Davis JM, Carver W (2007) Fractal and image analysis of morphological changes in the actin cytoskeleton of neonatal cardiac fibroblasts in response to mechanical stretch. Microsc Microanal 13: 133–143.
Gazit Y, Berk DA, Leunig M, Baxter LT, Jain, R K (1995) Scale-invariant behavior and vascular network formation in normal and tumor tissue. Phys Rev Lett 75: 2428–2431.
Gazit Y, Baish JW, Safabakhsh N, Leunig M, Baxter LT, Jain RK (1997) Fractal characteristics of tumor vascular architecture during tumor growth and regression. Microcirculation 4: 395–402.
Geiger B, Bershadsky A, Pankov R, Yamada KM (2001) Transmembrane crosstalk between the extracellular matrix- cytoskeleton crosstalk. Nat Rev Mol Cell Biol 2: 793–805.
Glucksmann A (1939) Studies on bone mechanics in vitro: II. The role of tension and pressure in chondrogenesis. Anat Rec 73: 39–56.
Goldsmith EC, Hoffman A, Morales MO, Potts JD, Price RL, McFadden A, Rice M, Borg TK (2004) Organization of fibroblasts in the heart. Develop Dyn 230: 787–794.
Grinnell F (2000) Fibroblast-collagen matrix contraction: growth factor signaling and mechanical loading. TRENDS Cell Biol 10: 362–365.
Grinnell F (2003) Fibroblast biology in three-dimensional collagen matrices. TRENDS Cell Biol 13: 264–269.
Grizzi F, Russo C, Colombo P, Franceschini B, Frezza EE, Cobos E, Chiriva-Internati M (2005) Quantitative evaluation and modeling of two-dimensional neovascular network complexity: the surface fractal dimension. BMC Cancer 5: 14–23.
Hall A. (1998) Rho GTPases and the actin cytoskeleton. Science 279: 509–514.
Heymans O, Blacher S, Brouers F, Pierard GE (1999) Fractal quantification of the microvasculature heterogeneity in cutaneous melanoma. Dermatology 198: 212–217.
Hu E, Lee D (2003) Rho kinase inhibitors as potential therapeutic agents for cardiovascular diseases. Curr Opin Investig Drugs 4: 1065–1075.
Hung CT, Williams JL (1994) A method for inducing equibiaxial and uniform strains in elastomeric membranes used as cell substrates. J Biomechanics 27: 227–232.
Janmey PA, Weitz DA (2004) Dealing with mechanics: mechanisms of force transduction in cells. Trends Biochem Sci 29: 364–370.
Kawamura S, Miyamoto S, Brown JH (2003) Initiation and transduction of stretch-induced RhoA and Rac1 activation through caveolae: cytoskeletal regulation of ERK translocation. J Biol Chem 278: 31111–31117.
Lammerding J, Kamm RD, Lee RT (2004) Mechanotransduction in cardiac myocytes. Ann NY Acad Sci 1015: 53–70.
Le Noble F, Moyon D, Pardanaud L, Yuan L, Djonov V, Matthijsen R, Breant C, Fleury V, Eichman A (2004) Flow regulates arterial-venous differentiation in the chick embryo yolk sac. Development 131: 361–375.
Lee AA, Delhaas T, McCulloch AD, Villarreal FJ (1999) Differential responses of adult cardiac fibroblasts to in vitro biaxial strain patterns. J Mol Cell Cardiol 31: 1833–1843.
Lee AA, Delhaas T, Waldman LK, MacKenna DA, Villarreal FJ, McCulloch AD (1996) An equibiaxial strain system for cultured cells. Am J Physiol 271: C1400–C1408.
Lee DJ, Ho C-H, Grinnell F (2003) LPA-stimulated fibroblast contraction of floating collagen matrices does not require Rho kinase activity or retraction of fibroblast extensions. Expt Cell Res 289: 86–94.
Leung DY, Glagov S and Matthews MB (1976) Cyclic stretching stimulates synthesis of matrix components by arterial smooth muscle cells in vitro. Science 191: 475–477.
Leung DYM, Glagof S, Matthews MB (1977) A new in vitro system for studying cell response to mechanical stimulation. Expt Cell Res 109: 285–298.
Lucitti JL, Jones EA, Huang C, Chen J, Fraser SE, Dickinson ME (2007) Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development 134: 3317–3326.
MacKenna DA, Dolfi F, Vuori K, Ruoslahti E (1998) Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts. J Clin Invest 101: 301–310.
Manser E. (2005) Rho GTPases in the organization of the actin cytoskeleton.In: Symons M, (ed.) Rho GTPases, New York: Kluwer Academic/Plenum Publishers, pp. 107–114.
Matthews BD, Overby DR, Mannix R, Ingber DE (2006) Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension and mechanosensitive ion channels. J Cell Sci 119: 508–518.
Michaelson D, Rush M, Philips MR (2005) Intracellular targeting of Rho family GTPases: implications of localization on function. In: Symons M, (ed.) Rho GTPases, New York: Kluwer Academic/Plenm Publishers, pp. 17–31.
Moldovan L, Moldovan NI, Sohn RH, Parikh SA, Goldschmidt-Clermont PJ (2000) Redox changes of cultured endothelial cells and actin dynamics. Circ Res 86: 549–557.
Moldovan L, Mythreye K, Goldschmidt-Clermont PJ, Satterwhite LL (2006) Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1. Cardiovasc Res 71: 236–246.
Nezadal M, Zemeskal O, Buchnicek M (2001) The box-counting: critical study, 4th conference on prediction, synergetic and more… The Faculty of Management, Institute of Information Technologies, Faculty of Technology, Tomas Bata University in Zlin, October 25–26. p18. HarFA software (http://www.fch.vutbr.cz/lectures/imagesci).
Pan J, Singh US, Takahashi T, Oka Y, Palm-Leis A, Herbelin BS, Baker KM. (2005) PKC mediates cyclic stretch-induced cardiac hypertrophy through Rho family GTPases and mitogen-activated protein kinases in cardiomyocytes. J Cell Physiol 202: 536–553.
Perona R, Montaner S, Saniger L, Sanchez-Perez I, Bravo R, Lacal JC (1997) Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins. Genes Dev 11: 463–475.
Porter KE, Turner NA, O‘regan DJ, Balmforth AJ, Ball SG (2004) Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res 61: 745–755.
Reithmacher D, Brinkmann V, Birchmeier C (1995) A targeted mutation in the mouse e-cadherin gene results in defective preimplantation development. Proc Natl Acad Sci USA 92: 855–859.
Ren J, Fang CX (2005) Small guanine nucleotide-binding protein Rho and myocardial function. Acta Pharmacol Sin 26: 279–285.
Ristanovic D, Nedeljkov V, Stefanovic BD, Milosevic NT, Grgurevic M, Stulic V (2002) Fractal and nonfractal analysis of cell images: comparison and application to neuronal dendritic arborization. Biol Cybern 87: 278–288.
Rodan GA, Mensi T, Harvey A (1975) A quantitative method for application of compressive forces to bone in tissue culture. Calcified Tissue Res 18: 125–131.
Rogers JA, Fuseler JW (2007) Regulation of NF-kappa B activation and nuclear translocation by exogenous nitric oxide (NO) donors in TNF-alpha activated vascular endothelial cells. Nitric Oxide 16: 379–391.
Sanchez-Esteban J, Wang Y, Filardo EJ, Rubin LP, Ingber DE (2006) Integrins beta1, alpha6, and alpha3 contribute to mechanical strain-induced differentiation of fetal lung type II epithelial cells via distinct mechanisms. Am J Physiol Lung Cell Mol Physiol 290: L343–L350.
Satoh S, Ueda Y, Koyanagi M, Kadokami T, Sugano M, Yoshikawa Y, Makino N (2003) Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heat failure. J Mol Cell Cardiol 35: 59–70.
Schaffer JL, Rizen M, L’Italien GJ, Benbrahim A, Megerman J, Gerstenfeld LC, Gray ML (1994) Device for the application of biaxially uniform and isotropic strain to a flexible cell culture membrane. J Orthop Res 12: 709–719.
Schmidt A, Hall MN. (1998) Signalling to the actin cytoskeleton. Annu Rev Cell Dev Biol 14: 305–338.
Sedivy R, Thurner S, Budinsky AC, Kostler WJ, Zielinski CC (2002) Short-term rhythmic proliferation of human breast cancer cell lines: surface effects and fractal growth patterns. J Pathol 197: 163–169.
Sulciner DJ, Irani K, Yu ZX, Ferrans VJ, Goldschmidt-Clermont P, Finkel T (1996) Rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation. Mol Cell Biol 16: 7115–7121.
Suematsu N, Satoh S, Kinugawa S, Tsutsui H, Hayashidani S, Nakamura R, Egashira K, Makino N, Takeshita A (2001) Alpha 1-adrenoceptor-Gq-RhoA signaling is upregulated to increase myofribillar Ca+2 sensitivity in failing hearts. Am J Physiol Heart Circ Physiol 281: H637–H646.
Thomason DB, Anderson O 3rd, Menon V (1996) Fractal analysis of cytoskeleton rearrangement in cardiac muscle during head-down tilt. J Appl Physiol 81: 1522–1527.
Ushio-Fukai M, Tang Y, Fukai T, Dikalov SI, Ma Y, Fujimoto M, Quinn MT, Pagano PJ, Johnson C, Alexander RW (2002) Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 91: 1160–1167.
Vasiliev JM (1991) Polarization of pseudopodial activities: cytoskeletal mechanisms. J Cell Sci 98: 1–4.
Walter Jr., RJ, Berns MW (1986) Digital image processing and analysis. In Inoue S, (ed.) Video Microscopy, New York and London: Plenum Press, pp. 327–392.
Wei L, Roberts W, Wang L, Yamada M, Zhang S, Zhao Z, Rivkees SA, Schwartz RJ, Imanaka-Yoshida K (2001) Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development 128: 2953–2962.
Wick N, Thurner S, Paiha K, Sedivy R, Vietor I, Huber LA (2003) Quantitative measurement of cell migration using time-lapse videomicroscopy and non-linear system analysis. Histochem Cell Biol 119: 15–20.
Yeh C, Rodan GA (1984) Tensile forces enhance PGE synthesis in osteoblasts grown on collagen ribbon. Calcif Tissue Int 36: 67–71.
Yoshigi M, Clark EB, Yost HJ (2003) Quantification of stretch-induced cytoskeletal remodeling in vascular endothelial cells by image processing. Cytometry A 55: 109–118.
Yost MJ, Simpson D, Wrona K, Ridley S, Ploehn HJ, Borg TK, Terracio L (2000) Design and construction of a uniaxial stretcher. Am J Physiol Heart Circ Physiol 279: H3124–H3130.
Yuan X-B, Jin M, Xu X, Song Y-Q, Wu C-P, Poo M-M, Duan S (2003) Signalling and crosstalk of Rho GTPases in mediating axon guidance. Nature Cell Biol 5: 38–43.
Zhang L, Liu JZ, Dean D, Sahgal V, Yue GH (2005) A three dimensional fractal analysis method for quantifying white matter structure in human brain. J Neurosci Methods 150: 242–253.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Carver, W., Fuseler, J.W. (2010). Mechanical Stretch-Induced Reorganization of the Cytoskeleton and the Small GTPase Rac-1 in Cardiac Fibroblasts. In: Kamkin, A., Kiseleva, I. (eds) Mechanosensitivity of the Heart. Mechanosensitivity in Cells and Tissues, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2850-1_2
Download citation
DOI: https://doi.org/10.1007/978-90-481-2850-1_2
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-2849-5
Online ISBN: 978-90-481-2850-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)