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

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.

A first step towards recognizing the fundamental role of smooth muscle tone in large artery (dys)function?

“…Indeed, many animal studies have shown that aortic contraction can be elicited upon stimulation with vasoactive drugs/agents, both ex vivo and in vivo [5,9,10]. Furthermore, we have suggested that such contraction may play a pivotal role in preventing maladaptation and fibrotic remodelling of the aorta in angiotensin II-induced hypertension in mice [9].…”

“…Collagen fibres, on the other hand, because of their wavy arrangement in unloaded arteries, get recruited at higher pressures and their gradual uncrimping leads to a nearly exponential pressure-diameter relationship (Fig. 1, hatched area) [9,14,15,17]. Modelling SMC contraction is considerably more complex.…”

“…Despite this classification, the boundary between these two arterial phenotypes is blurred as mechanical properties and wall composition change gradually while moving away from the heart [6][7][8]. Furthermore, SMCs constitute a considerable portion of the wall volume also in the aorta [6,8,9], so that, although often overlooked, their role in the mechanics of elastic arteries should not be neglected. Indeed, many animal studies have shown that aortic contraction can be elicited upon stimulation with vasoactive drugs/agents, both ex vivo and in vivo [5,9,10].…”

“…Furthermore, SMCs constitute a considerable portion of the wall volume also in the aorta [6,8,9], so that, although often overlooked, their role in the mechanics of elastic arteries should not be neglected. Indeed, many animal studies have shown that aortic contraction can be elicited upon stimulation with vasoactive drugs/agents, both ex vivo and in vivo [5,9,10]. Furthermore, we have suggested that such contraction may play a pivotal role in preventing maladaptation and fibrotic remodelling of the aorta in angiotensin II-induced hypertension in mice [9].…”

Comparative Study of Human and Murine Aortic Biomechanics and Hemodynamics in Vascular Aging

“…Because we used population-based data for a particular mouse colony, our results hold for the C57BL/6 × 129/SvEv strain, with expected differences for pure C57BL/6 and 129/SvEv mice (cf. Spronck et al, 2021 ). Previous work has characterized regional aortic biomechanics in multiple mouse models, though without associated FSI analyses of the central hemodynamics ( Ferruzzi et al, 2013 ; Bersi et al, 2017 ; Murtada et al, 2020 ; Spronck et al, 2020 ).…”