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

Abstract

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 mechanotransduction. It is demonstrated that a mechano-transducer that 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.

Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction

“…Rac1 activation occurred at sites of AJs experiencing the highest tension in response to fluid shear stress ( Allen et al, 2011 ; Liu et al, 2013 ), suggesting that Rac1 functions by opposing the tension developed across VE-cadherin adhesion through counterbalancing RhoA activity ( Fig. 4 A ).…”

A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress

“…The mechanisms that determine polarity, including that of Rac1, in response to shear stress is a longstanding question in the field and is an intense area of study. Recent work modeling polarized Rac1 activation in ECs predicts that an endothelial cell in a confluent monolayer would experience compression at the upstream edge of the cell and tension at the downstream edge when exposed to flow (Allen et al, 2011). Therefore, mechanosensitive Iden et al, 2006;Tyler et al, 2010).…”