Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice

B. Spronck*, M. Latorre, M. Wang, S. Mehta, A.W. Caulk, P.W. Ren, A.B. Ramachandra, S.I. Murtada, A. Rojas, C.S. He, B. Jiang, M.R. Bersi, G. Tellides, J.D. Humphrey*

*Corresponding author for this work

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Abstract

Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.
Original languageEnglish
Article number20210336
Number of pages11
JournalJournal of the Royal Society Interface
Volume18
Issue number180
DOIs
Publication statusPublished - 28 Jul 2021

Keywords

  • aorta
  • fibrosis
  • stiffness
  • inflammation
  • contractility
  • C57BL
  • 6 J
  • 129S6
  • SvEvTac
  • smooth muscle phenotype
  • SMOOTH-MUSCLE-CELLS
  • ANGIOTENSIN-II
  • ARTERIAL ADAPTATIONS
  • COLLAGEN-SYNTHESIS
  • AT(1) RECEPTOR
  • VASCULAR WALL
  • ACTIVATION
  • ACCUMULATION
  • HYPERTROPHY
  • INVOLVEMENT

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