GENETIC BACKGROUND DOMINATES FIBROTIC AORTIC REMODELING DURING ANGIOTENSIN-INDUCED HYPERTENSION IN MICE

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Objective: Many induced genetic mutations affect aortic structure and function in mice, but less is known about the influence of background strain. This study quantifies and compares the aortic phenotype in angiotensin II (AngII)-induced hypertension across different strains of wild-type mice. Design and method: Adult 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 in both strains (+34% vs. +32%, systolic). Excised descending thoracic aortas were subjected to a series of isobaric vasocontraction and vasorelaxation tests as well as novel biaxial stiffness testing. Immuno-histological studies quantified medial and adventitial composition as well as CD45+ cellular infiltration. Results: 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 (+89% thickness increase) but under-adaptive remodeling in 129SvEv mice (+12% thickness increase). Importantly, vasoconstrictive strength was lower in C57BL/6J than 129SvEv mice, both before (-4% vs. -11% contractile change in outer diameter (δOD), p = 0.020; -8 vs. -24% contractile change in circumferential stress (δσ), p = 0.023) and after (-10% vs. -22% contractile δOD, p < 0.001; -24 vs. -46% contractile δσ, p < 0.001) hypertension. CD45+ cell content was markedly higher in C57BL/6J than 129SvEv mice following hypertension (p < 0.001). When considering individual vessels, wall thickness correlated with both CD45+ content (p = 0.034) and total contractility (p = 0.001), with contractility the strongest predictor statistically. Finally, layer-specific biomechanical analyses revealed increased adventitial load bearing in the hypertensive 129SvEv aorta under passive conditions, which, however, it is able to normalize by its increased contractility. Conclusions: Genetic modifiers play key roles in the different hypertensive aortic remodeling between C57BL/6J and 129SvEv mice (Figure) as well as mixed C57BL/6;129SvEv mice. The lower fibrotic response in 129SvEv mice results from their lower inflammatory state but also their greater aortic vasoresponsiveness to AngII, which lowers the wall-stress associated mechano-stimulus for remodeling. Remodeling in mixed-background mice was dominated by the 129SvEv strain.