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bioRxiv · 10.1101/727800

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

Spronck, B.·Caulk, A. W.·Ramachandra, A. B.·Murtada, S.-I.·Rojas, A.·He, C.-S.·Bersi, M. R.·Tellides, G.·Humphrey, J. D.
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Abstract

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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/727800v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@e9f1d9org.highwire.dtl.DTLVardef@104e221org.highwire.dtl.DTLVardef@19a00bforg.highwire.dtl.DTLVardef@1a70cd5_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Spronck, B., Caulk, A. W., Ramachandra, A. B., Murtada, S.-I., Rojas, A., He, C.-S., Bersi, M. R., Tellides, G., Humphrey, J. D.. 2019-08-15. Genetic Background Dominates Fibrotic Aortic Remodeling During Angiotensin-Induced Hypertension in Mice. https://doi.org/10.1101/727800

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