Rho Mediates the Shear-Enhancement of Endothelial Cell Migration and Traction Force Generation

Shiu, Yan Ting; Li, Song; Marganski, William A.; Usami, Shunichi; Schwartz, Martin A.; Wang, Yu Li; Dembo, Micah; Chien, Shu

doi:10.1016/s0006-3495(04)74311-8

Cited by 135 publications

(132 citation statements)

References 37 publications

(64 reference statements)

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“…Many laboratories are attempting to determine how motility-related signals might be connected (often in two-way fashion) to the proximally governing biophysical mechanisms (22,27,28). Because of the great complexity of biochemical signaling networks and of their connections to biophysical mechanisms by which cell functional responses such as motility are conducted (29), we are convinced that construction of cell signal-response models will require multivariate computational analysis (30, 31).…”

Section: Resultsmentioning

confidence: 99%

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Zaman

Trapani

Sieminski

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

1,052

1,005

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Cell migration on 2D surfaces is governed by a balance between counteracting tractile and adhesion forces. Although biochemical factors such as adhesion receptor and ligand concentration and binding, signaling through cell adhesion complexes, and cytoskeletal structure assembly/disassembly have been studied in detail in a 2D context, the critical biochemical and biophysical parameters that affect cell migration in 3D matrices have not been quantitatively investigated. We demonstrate that, in addition to adhesion and tractile forces, matrix stiffness is a key factor that influences cell movement in 3D. Cell migration assays in which Matrigel density, fibronectin concentration, and β1 integrin binding are systematically varied show that at a specific Matrigel density the migration speed of DU-145 human prostate carcinoma cells is a balance between tractile and adhesion forces. However, when biochemical parameters such as matrix ligand and cell integrin receptor levels are held constant, maximal cell movement shifts to matrices exhibiting lesser stiffness. This behavior contradicts current 2D models but is predicted by a recent force-based computational model of cell movement in a 3D matrix. As expected, this 3D motility through an extracellular environment of pore size much smaller than cellular dimensions does depend on proteolytic activity as broad-spectrum matrix metalloproteinase (MMP) inhibitors limit the migration of DU-145 cells and also HT-1080 fibrosarcoma cells. Our experimental findings here represent, to our knowledge, discovery of a previously undescribed set of balances of cell and matrix properties that govern the ability of tumor cells to migration in 3D environments.

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Section: Resultsmentioning

confidence: 99%

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Zaman

Trapani

Sieminski

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

1,052

1,005

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“…Therefore, cell migration shows a maximum speed at the intermediate level of adhesiveness [Duband et al, 1991;DiMilla et al, 1993;Keely et al, 1995]. We have shown that EC migration on fibronectin (0.5-40 mg/cm 2 ) has a biphasic dependency on the density, with highest migration speed at $5 mg/cm 2 [Shiu et al, 2004]. Shear stress increases the migration speed at both high and low densities, suggesting that shear stress may enhance the adhesion at the front on the low fibronectin density and the detachment at the rear on the high fibronectin density.…”

Section: Ecm In Mechanotransductionmentioning

confidence: 75%

“…In addition, inhibition of Rho blocks directional migration under flow, but enhances migration speed, possibly by decreasing cell-ECM adhesions [Wojciak-Stothard and Ridley, 2003]. Since complete inhibition of Rho or p160ROCK disrupts actin filaments and inhibits EC migration Shiu et al, 2004], a medium level of Rho activity may be needed for the most efficient EC migration. Rho activity is also required for the generation of traction force through actin fibers and cell-ECM adhesions in response to shear stress [Shiu et al, 2003] (see the section on ''Roles of Integrins and Proteoglycans in Shear StressInduced EC Migration'').…”

Section: Cytoskeleton As Mechano-effectormentioning

confidence: 99%

Mechanotransduction in endothelial cell migration

Li¹,

Huang²,

Hsu³

2005

J of Cellular Biochemistry

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237

180

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The migration of endothelial cells (ECs) plays an important role in vascular remodeling and regeneration. EC migration can be regulated by different mechanisms such as chemotaxis, haptotaxis, and mechanotaxis. This review will focus on fluid shear stress-induced mechanotransduction during EC migration. EC migration and mechanotransduction can be modulated by cytoskeleton, cell surface receptors such as integrins and proteoglycans, the chemical and physical properties of extracellular matrix (ECM) and cell-cell adhesions. The shear stress applied on the luminal surface of ECs can be sensed by cell membrane and associated receptor and transmitted throughout the cell to cell-ECM adhesions and cell-cell adhesions. As a result, shear stress induces directional migration of ECs by promoting lamellipodial protrusion and the formation of focal adhesions (FAs) at the front in the flow direction and the disassembly of FAs at the rear. Persistent EC migration in the flow direction can be driven by polarized activation of signaling molecules and the positive feedback loops constituted by Rho GTPases, cytoskeleton, and FAs at the leading edge. Furthermore, shear stressinduced EC migration can overcome the haptotaxis of ECs. Given the hemodynamic environment of the vascular system, mechanotransduction during EC migration has a significant impact on vascular development, angiogenesis, and vascular wound healing.

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“…External forces can cause adhesion reinforcement (17)(18)(19) and stress fiber formation (20) to strengthen traction forces and appear to initiate specific signaling pathways that may provide feedback to regulate myosin activity (3,21). Thus, it remains unclear whether external forces act directly or also depend on mechanically induced changes in traction forces to exert their cellular effects.…”

mentioning

confidence: 99%

Magnetic microposts as an approach to apply forces to living cells

Sniadecki

Anguelouch

Yang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

312

315

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Cells respond to mechanical forces whether applied externally or generated internally via the cytoskeleton. To study the cellular response to forces separately, we applied external forces to cells via microfabricated magnetic posts containing cobalt nanowires interspersed among an array of elastomeric posts, which acted as independent sensors to cellular traction forces. A magnetic field induced torque in the nanowires, which deflected the magnetic posts and imparted force to individual adhesions of cells attached to the array. Using this system, we examined the cellular reaction to applied forces and found that applying a step force led to an increase in local focal adhesion size at the site of application but not at nearby nonmagnetic posts. Focal adhesion recruitment was enhanced further when cells were subjected to multiple force actuations within the same time interval. Recording the traction forces in response to such force stimulation revealed two responses: a sudden loss in contractility that occurred within the first minute of stimulation or a gradual decay in contractility over several minutes. For both types of responses, the subcellular distribution of loss in traction forces was not confined to locations near the actuated micropost, nor uniformly across the whole cell, but instead occurred at discrete locations along the cell periphery. Together, these data reveal an important dynamic biological relationship between external and internal forces and demonstrate the utility of this microfabricated system to explore this interaction.focal adhesions ͉ magnetic nanowires ͉ mechanotransduction ͉ microfabrication ͉ traction forces

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Rho Mediates the Shear-Enhancement of Endothelial Cell Migration and Traction Force Generation

Cited by 135 publications

References 37 publications

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Mechanotransduction in endothelial cell migration

Magnetic microposts as an approach to apply forces to living cells

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