P.58 Genetic Background Dictates Aortic Fibrosis in Hypertensive Mice

DOI

10.2991/artres.k.201209.068How to use a DOI?

Keywords

Stiffness; smooth muscle; inflammation

Abstract

Background: Many genetic mutations affect aortic structure and function in mice, but little is known about the influence of background strain. We compared the biomechanical, structural, and gene expression responses of C57BL/6J and 129SvEv aortas to angiotensin II (AngII)-induced hypertension.

Methods: After AngII infusion (14-day, 1000 ng/kg/min) and euthanasia, excised thoracic aortas were characterized functionally using isobaric vasoactive and cyclic passive stiffness tests. Immunohistochemistry quantified medial/adventitial composition and infiltration of pan-inflammatory CD45⁺ cells. RNA sequencing-based gene ontology, wall stress analyses, and growth and remodeling (G&R) simulations were performed to complement our mechanical findings.

Results: Baseline aortic geometry, composition, and biomechanical properties, as well as AngII-induced blood pressure increases (+34% vs. +32%, systolic), were similar across strains. Yet, AngII-induced aortic remodeling differed dramatically, with gross maladaptive, fibrotic remodeling (exuberant medial/adventitial thickening) in C57BL/6J but not in 129SvEv mice (+89% vs. +12% thickness increase, p = 0.022). CD45⁺ cell density was markedly higher in hypertensive C57BL/6J than 129SvEv aortas (p = 0.001), while vasoconstrictive responses to AngII (causing a wall stress decrease Δσ) were greater in 129SvEv than C57BL/6J mice, both before (Δσ = −8 vs. −24%, p = 0.023) and after (Δσ = −24 vs. −46%, p < 0.001) hypertension. Gene expression, stress analyses, and G&R simulations reinforced 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 (Figure).

Conclusions: Differentially expressed mechano-sensitive genes 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.

Copyright

© 2020 Association for Research into Arterial Structure and Physiology. Publishing services by Atlantis Press International B.V.

Open Access

This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

TY  - JOUR
AU  - Bart Spronck
AU  - Marcos Latorre
AU  - Sameet Mehta
AU  - Alexander W. Caulk
AU  - Abhay B. Ramachandra
AU  - Sae-Il Murtada
AU  - Alexia Rojas
AU  - Chang-Sun He
AU  - Bo Jiang
AU  - Mo Wang
AU  - Matthew R. Bersi
AU  - George Tellides
AU  - Jay D. Humphrey
PY  - 2020
DA  - 2020/12/31
TI  - P.58 Genetic Background Dictates Aortic Fibrosis in Hypertensive Mice
JO  - Artery Research
SP  - S81
EP  - S82
VL  - 26
IS  - Supplement 1
SN  - 1876-4401
UR  - https://doi.org/10.2991/artres.k.201209.068
DO  - 10.2991/artres.k.201209.068
ID  - Spronck2020
ER  -