Shear-induced force transmission in a multicomponent, multicell model of the endothelium

Abstract

Haemodynamic forces applied at the apical surface of vascular endothelial cells (ECs) provide the mechanical signals at intracellular organelles and through the inter-connected cellular network. The objective of this study is to quantify the intracellular and intercellular stresses in a confluent vascular EC monolayer. A novel three-dimensional, multiscale and multicomponent model of focally adhered ECs is developed to account for the role of potential mechanosensors (glycocalyx layer, actin cortical layer, nucleus, cytoskeleton, focal adhesions (FAs) and adherens junctions (ADJs)) in mechanotransmission and EC deformation. The overriding issue addressed is the stress amplification in these regions, which may play a role in subcellular localization of mechanotransmission. The model predicts that the stresses are amplified 250-600-fold over apical values at ADJs and 175-200-fold at FAs for ECs exposed to a mean shear stress of 10 dyne cm 22 . Estimates of forces per molecule in the cell attachment points to the external cellular matrix and cell-cell adhesion points are of the order of 8 pN at FAs and as high as 3 pN at ADJs, suggesting that direct force-induced mechanotransmission by single molecules is possible in both. The maximum deformation of an EC in the monolayer is calculated as 400 nm in response to a mean shear stress of 1 Pa applied over the EC surface which is in accord with measurements. The model also predicts that the magnitude of the cell-cell junction inclination angle is independent of the cytoskeleton and glycocalyx. The inclination angle of the cell-cell junction is calculated to be 6.68 in an EC monolayer, which is somewhat below the measured value (9.98) reported previously for ECs subjected to 1.6 Pa shear stress for 30 min. The present model is able, for the first time, to cross the boundaries between different length scales in order to provide a global view of potential locations of mechanotransmission.

Development of a two-stage limb ischemia model to better simulate human peripheral artery disease

“…Shear stress promotes arteriogenesis by stimulating remodelling of collaterals 67,68 . Endothelial cells transduce changes in shear stress into intracellular signals which promote expression of a distinct set of genes which can control the response to ischemia [69][70][71] . Previous studies suggest that increased shear stress promotes phosphorylation and upregulation of mechano-sensors, such as TRPV4 [72][73][74][75] .…”

Mechanotransmission in endothelial cells subjected to oscillatory and multi-directional shear flow

“…The cytoskeleton, in this study, is modelled as a network of viscoelastic stress fibres (SFs) that are peripherally and centrally distributed, based on the observations of Thoumine et al [10]. Other components of the cytoskeleton, most notably, microtubules and intermediate filaments, are not included in the model, but effective properties are used for the cytoplasm, which considers the influence of these components [12]. The arrangement of SFs is shown in figure 1c which demonstrates that SFs emanate from the apical plasma membrane and link to FAs or the nucleus or intercellular junctions.…”

“…The arrangement of SFs is shown in figure 1c which demonstrates that SFs emanate from the apical plasma membrane and link to FAs or the nucleus or intercellular junctions. One SF connects each FA on the basal side of the cell to the apical plasma membrane; one SF connects each FA on the basal side of the cell to the nucleus; one SF connects each ADJ to the apical plasma membrane [12,20,26,27,39,40,43]. The mechanical linkage between the apical surface and the nucleus also exists through the effective viscoelastic properties used for the cytoplasm [12].…”

“…Responses of ECs to haemodynamic forces play a significant role in vascular health and disease [3,4], and models of EC mechanics have evolved significantly since the early studies of Fung & Liu [5]. ECs transduce the FSS resulting from blood flow into intracellular signals that affect gene expression and cellular functions such as proliferation, apoptosis, migration, permeability, cell alignment and mechanical properties [6][7][8][9][10][11][12]. Numerous sites have been implicated in transducing mechanical stresses, including the plasma membrane [5,6,9,[12][13][14][15] and its associated glycocalyx [12,[16][17][18][19], focal adhesions (FAs) [10,12,[20][21][22][23][24][25][26], the nucleus [27,28], the cytoskeleton [6,12,16,29,30], the cortical membrane [1,12,31,32] and the intercellular junctions [33][34][35]…”

“…Such computational models are unique as no experiment can reveal the cellular force transmission in such detail. The model of Dabagh et al [12] treated all cellular components as incompressible neo-Hookean materials; viscoelastic effects were not considered. Gouget et al [37] developed a model of mechanical signal transmission within a cell by describing strains in a network of pre-stressed viscoelastic stress fibres following the application of a force to the cell surface.…”