Multiscale Model Reveals Importance Of Cumulative Vascular Smooth Muscle Cell Responses In Aortic Hypercontractility

Diabetes more than doubles the risk of cardiovascular disease (CVD), and the chronic hyperglycemia leads to vascular maladaptations prior to the diagnostic threshold. While endothelium-independent vascular smooth muscle cell (VSMC) hypercontractility is well-established at the tissue-scale, the mechanical phenotype is inconsistently observed at the cell-scale. Our strategy consisted of experimental characterization at the tissue-scale via an isometric ring contraction assay of WT and OGT KO aortas, the latter an established chronic hyperglycemia model, from male mice and at the cell-scale via published cellular microbiaxial stretching data, coupled with the construction of a multiscale computational model. We hypothesize that the biochemical signaling changes due to increased blood glucose are sufficient to predict VSMC hypercontractility. The multiscale model operates off a biochemical signaling network that determines the activation and contraction of actin stress fibers. The stress fibers are connected in either 2D (cell-scale) or 3D (tissue-scale) cytoskeletal networks where for the tissue-scale, the cytoskeletal mechanics are fit to a macroscale constrained mixture model. The multiscale model correctly predicts the cell-scale euglycemic contractility, however the hyperglycemic condition is too subtle to be resolved at this scale. At the tissue-scale, the model correctly predicts both euglycemic and hyperglycemic active force generation. The model does not currently consider ECM alterations, so the changes in passive tissue mechanics cannot be predicted. The model predictions suggest that while the impetus of hyperglycemia-driven hypercontractility occurs at the cell-scale, these small-scale changes must be amplified across length scales to be experimentally-observable. These results demonstrate the power of the multiscale model to connect cell- and tissue-scale vascular mechanical phenotypes due to chronic hyperglycemia.