Intracellular signaling control of mechanical homeostasis in the aorta.

Mature arteries exhibit a preferred biomechanical state in health evidenced by a narrow range of intramural and wall shear stresses. When stresses are perturbed by changes in blood pressure or flow, homeostatic mechanisms tend to restore target values via altered contractility and/or cell and matrix turnover. In contrast, vascular disease associates with compromised homeostasis, hence we must understand mechanisms underlying mechanical homeostasis and its robustness. Here, we use a multiscale computational model wherein mechanosensitive intracellular signaling pathways drive arterial growth and remodeling. First, we identify an ensemble of cell-level parameterizations where tissue-level responses are well-regulated and adaptive to hemodynamic perturbations. The responsible mechanism is persistent multiscale negative feedback whereby mechanosensitive signaling drives mass turnover until homeostatic target stresses are reached. This demonstrates how robustness emerges despite inevitable cell and individual heterogeneity. Second, we investigate tissue-level effects of signaling node knockdowns (ATIR, ROCK, TGF[Formula: see text]RII, PDGFR, ERK1/2) and find general agreement with experimental reports of fault tolerance. Robustness against structural changes manifests via low engagement of the node under baseline stresses or compensatory multiscale feedback via upregulation of additional pathways. Third, we show how knockdowns affect collagen and smooth muscle turnover at baseline and with perturbed stresses. In several cases, basal production is not remarkably affected, but sensitivities to stress deviations, which influence feedback strength, are reduced. Such reductions can impair adaptive responses, consistent with previously reported aortic vulnerability despite grossly normal appearances. Reduced stress sensitivities thus form a candidate mechanism for how robustness is lost, enabling transitions from health towards disease.