A model of localised Rac1 activation in endothelial cells due to fluid flow

• Published in: Journal of theoretical biology Vol. 280; no. 1; pp. 34 - 42
• Main Authors: Allen, R.J., Bogle, I.D.L., Ridley, A.J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 07-07-2011; Elsevier
• Subjects: actin; Actin Cytoskeleton - metabolism; Animals; Cell Polarity - physiology; cytoskeleton; Endothelial cell; endothelial cells; Endothelial Cells - enzymology; Enzyme Activation; guanosinetriphosphatase; Humans; Life Sciences; Mechanotransduction, Cellular - physiology; Models, Biological; Pseudopodia - metabolism; rac1 GTP-Binding Protein - metabolism; receptors; Rho GTPases; Shear stress; Src; Stokes flow; Shear stress; Endothelial cell; Rho GTPases; Src; Stokes flow; Shear Stress; Endothelial Cell; Stokes Flow
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2011.03.021

Endothelial cells respond to fluid flow by elongating in the direction of flow. Cytoskeletal changes and activation of signalling molecules have been extensively studied in this response, including: activation of receptors by mechano-transduction, actin filament alignment in the direction of flow, changes to cell-substratum adhesions, actin-driven lamellipodium extension, and localised activation of Rho GTPases. To study this process we model the force over a single cell and couple this to a model of the Rho GTPases, Rac and Rho, via a Kelvin-body model of mechano-transduction. It is demonstrated that a mechano-transducer can respond to the normal component of the force is likely to be a necessary component of the signalling network in order to establish polarity. Furthermore, the rate-limiting step of Rac1 activation is predicted to be conversion of Rac-GDP to Rac-GTP, rather than activation of upstream components. Modelling illustrates that the aligned endothelial cell morphology could attenuate the signalling network.