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Adherent cells are generally able to reorient in response to cyclic strain. In three-dimensional tissues, however, extracellular collagen can affect this cellular response. In this study, a computational model able to predict the combined effects of mechanical stimuli and collagen on cellular (re)orientation was developed. In particular, a recently proposed computational model (which only accounts for mechanical stimuli) was extended by considering two hypotheses on how collagen influences cellular (re)orientation: collagen contributes to cell alignment by providing topographical cues (contact guidance); or collagen causes a spatial obstruction for cellular reorientation (steric hindrance). In addition, we developed an evolution law to predict cell-induced collagen realignment. The hypotheses were tested by simulating bi- or uniaxially constrained cell-populated collagen gels with different collagen densities, subjected to immediate or delayed uniaxial cyclic strain with varying strain amplitudes. The simulation outcomes are in agreement with previous experimental reports. Taken together, our computational approach is a promising tool to understand and predict the remodeling of collagenous tissues, such as native or tissue-engineered arteries and heart valves.

Tissue growth and remodeling are known to govern mechanical homeostasis in biological tissue, but their relative contributions to homeostasis remain unclear. Here, we use mechanical models, fueled by experimental findings, to demonstrate that growth and remodeling have different effects on heart valve stretch homeostasis during physiological postnatal development. Two developmental stages were considered: early-stage (from infant to adolescent) and late-stage (from adolescent to adult) development. Our models indicated that growth and remodeling play opposing roles in preserving tissue stretch and with time. During early-stage development, excessive tissue stretch was decreased by tissue growth and increased by remodeling. In contrast, during late-stage development tissue stretch was decreased by remodeling and increased by growth. Our findings contribute to an improved understanding of native heart valve adaptation throughout life, and are highly relevant for the development of tissue-engineered heart valves.

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall.