Genetic Background Dominates Fibrotic Aortic Remodeling During Angiotensin-Induced Hypertension In Mice

ObjectiveMany 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 wild-type mice.nnApproach and ResultsAdult 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.nnConclusionsGenetic 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.nnGraphical AbstractnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC=\"FIGDIR/small/727800v1_ufig1.gif\" ALT=\"Figure 1\"\u003enView larger version (69K):norg.highwire.dtl.DTLVardef@b395b5org.highwire.dtl.DTLVardef@29c56aorg.highwire.dtl.DTLVardef@5fc3aborg.highwire.dtl.DTLVardef@1274308_HPS_FORMAT_FIGEXP M_FIG C_FIG