Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.

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Objective. Many genetically-induced mutations affect aortic structure and function in mice, but little is known about the influence of background strain. This study quantifies the aortic phenotype in angiotensin II (AngII)-induced hypertension across different strains of wildtype mice.Approach and Results. Adult male C57BL/6J and 129SvEv mice were studied before and after induction of hypertension via subcutaneous infusion of AngII (1000 ng/kg/min) for two weeks, which elevated blood pressure similarly (+31% vs. +32%, systolic). The descending thoracic aortas were placed within a custom computer-controlled biomechanical testing device and subjected to a series of isobaric vasocontraction and vasorelaxation tests as well as novel stiffness testing. Immuno-histological studies quantified medial and adventitial composition as well as CD45 + cellular infiltration. Baseline aortic geometry and biomechanical properties were similar across strains, consistent with the existence of general homeostatic mechanical targets.Nevertheless, aortic remodeling due to AngII-induced hypertension differed dramatically between strains, with gross over-adaptive remodeling (exuberant thickening of the media and adventitia) in C57BL/6J but under-adaptive remodeling in 129SvEv mice. Importantly, vasoconstrictive strength was lower in C57BL/6J than 129SvEv mice, both before and after hypertension, while CD45 + cell content was markedly higher in C57BL/6J than 129SvEv mice following hypertension. Conclusions.Genetic modifiers likely play a key role in the different hypertensive aortic remodeling between C57BL/6J and 129SvEv mice as well as mixed C57BL/6;129SvEv mice. The lower fibrotic response in 129SvEv mice results from their lower inflammatory state but also greater aortic vasoresponsiveness to AngII, which lowers the wall-stress mechano-stimulus for remodeling. Remodeling in mixed background mice is dominated by the 129SvEv strain. φ m smooth muscle cross-sectional area fraction φ g ground substance/glycosaminoglycan cross-sectional area fraction We are grateful for our prior collaborations with Drs. Jacopo Ferruzzi, Hiromi Yanagisawa, Chiara Bellini, and Dianna M. Milewicz that yielded data for C57BL/6;129SvEv (i.e., Fbln5 +/+ and Myh11 +/+ ) mice (Ferruzzi et al, 2015; Bellini et al., 2015) and, so too, with Dr. David G. Harrison for data for low-rate (490 ng/kg/min) AngII infusion of C57BL/6 mice (Bersi et al., 2016), whichwere used herein as consistent quantitative comparators. We further acknowledge the Yale Pathology Tissue Services for histology and immunohistochemistry.