RT Journal Article SR Electronic T1 Genetic Background Dictates Aortic Fibrosis in Hypertensive Mice JF bioRxiv FD Cold Spring Harbor Laboratory SP 727800 DO 10.1101/727800 A1 Bart Spronck A1 Marcos Latorre A1 Sameet Mehta A1 Alexander W. Caulk A1 Abhay B. Ramachandra A1 Sae-Il Murtada A1 Alexia Rojas A1 Chang-Shun He A1 Bo Jiang A1 Mo Wang A1 Matthew R. Bersi A1 George Tellides A1 Jay D. Humphrey YR 2020 UL http://biorxiv.org/content/early/2020/05/05/727800.abstract AB Many genetic mutations affect aortic structure and function in mice, but little is known about the influence of background strain. We phenotyped aortas from C57BL/6J and 129SvEv mice before and after continuous infusion of angiotensin II (AngII) for two weeks, which elevated blood pressure similarly in both strains (1.34-fold vs. 1.32-fold, systolic). Excised thoracic aortas were characterized functionally using isobaric vasoactive and cyclic passive stiffness tests whereas immunohistological studies quantified altered medial and adventitial composition as well as the infiltration of pan-inflammatory CD45+ cells. Baseline aortic geometry, composition, and biomechanical properties were similar across strains, consistent with mechanical homeostasis. Yet, aortic remodeling in response to AngII-induced hypertension differed dramatically between strains, with gross maladaptive remodeling in C57BL/6J but not in 129SvEv mice. CD45+ cell density was markedly higher in C57BL/6J than 129SvEv aortas while vasoconstrictive responses to AngII were greater in 129SvEv than C57BL/6J both before and after hypertension; importantly, smooth muscle mediated vasoconstriction reduces pressure-induced wall stress. Bulk RNA sequencing, layer-specific biomechanical modeling, and growth and remodeling simulations support the emergent hypothesis that mechanical stress-mediated immune processes promote maladaptive remodeling while smooth muscle contractile processes reduce wall stress and thereby protect against fibrosis. Differentially expressed mechano-sensitive genes thus play key roles in the distinct hypertensive aortic remodeling in C57BL/6J and 129SvEv mice and must be considered when comparing studies in different background strains, particularly mixed strains that are often used to generate mice with targeted mutations.Competing Interest StatementThe authors have declared no competing interest.