Figure 6. Predictive computational model of cardiac fibroblasts in response to tension indicates mechanosensory responses.

For the tension dose‐response simulations, tension stimulation was applied at graduating intervals of 10% activation from 0% (static, A) to 100% (B) until species steady‐state activation levels were achieved. The condensed network reconstruction (A and B) and species heatmap (C) were based on the steady‐state species activation levels derived from these simulations. Cardiac fibroblasts, in response to high tension stimulation (tension activation=90%), showed a robust activation of profibrotic signaling pathways (B and C). Tension stimulation was integrated into the cardiac fibroblast (CF) signaling network dynamics through the primary cilia and β‐integrin nodes. Expected increases in canonical and noncanonical TGFβ signaling as well as fibrosis‐related transcription factors (myocardin related transcription factor [MRTF], connective tissue growth factor [CTGF], yes‐associated protein [YAP], serum response factor [SRF], mothers against decapentaplegic homolog 3 [Smad3], extracellular related kinase [Erk]) are shown and are associated with increased collagen‐1, 3, and α‐smooth muscle actin (α‐SMA) activity (C). A positive dose‐response relationship is evident between the CF profibrotic response and tension stimulation but inversely related to primary cilia and ADP ribosylation factor like GTPase 13B (ARL13B) (C).