Maladaptive aortic remodeling in hypertension associates with dysfunctional smooth muscle contractility

Abstract

Intramural cells are responsible for establishing, maintaining, and restoring the functional capability and structural integrity of the aortic wall. In response to hypertensive loading, these cells tend to increase wall content via extracellular matrix turnover in an attempt to return wall stress and/or material stiffness toward homeostatic values despite the elevated pressure. Using a common rodent model of induced hypertension, we found marked mouse-to-mouse differences in thoracic aortic remodeling over 2–4 wk of pressure elevation, with mechanoadaptation in some but gross maladaptation in most mice despite the same experimental conditions and overall genetic background. Consistent with our hypothesis, we also found a strong correlation between maladaptive aortic remodeling and a dysfunctional ability of the vessel to vasoconstrict, with maladaptation often evidenced by marked adventitial fibrosis. Remarkably, mouse-to-mouse variability did not correlate with the degree or duration of pressure elevation over the 2- to 4-wk study period. These findings suggest both a need to study together the structure, mechanical properties, and function across layers of the wall when assessing aortic health and a need for caution in using common statistical comparisons across small seemingly well-defined groups that may mask important underlying individual responses, an area of investigation that demands increasing attention as we move toward an era of precision diagnosis and patient care. NEW & NOTEWORTHY There are three primary findings. Marked mouse-to-mouse differences exist in large vessel hypertensive remodeling in an otherwise equivalent cohort of animals. The degree of maladaptation correlates strongly with decreases in smooth muscle contractile capacity. Finally, short-term maladaptive remodeling is independent of the precise degree or duration of the pressure elevation provided that thresholds are exceeded. Therapeutic targets should thus be personalized and focus on both layer-to-layer interactions and early interventions.

Genetic Background Dictates Aortic Fibrosis in Hypertensive Mice

“…= ( , )/ℎ( , )). The role of smooth muscle contraction is consistent with a recent finding in a larger cohort of C57BL/6 mice wherein a small sub-set of DTAs having modest AngII-induced hypertensive remodeling had a well preserved vasoactive capability, at least to KCl (Korneva and Humphrey, 2019). This observation is also consistent with our prior report of regional differences in AngII-induced hypertensive aortic remodeling in Apoe -/mice wherein maladaptive fibrotic remodeling manifested in regions having a lower intrinsic vasoresponsiveness to AngII (Bersi et al, 2017).…”

“…AngII-induced hypertensive remodeling in C57BL/6 DTAs tends not to differ over two-to-four weeks of infusion (Bersi et al, 2016;Korneva and Humphrey, 2019) and that hypertension induced in C57BL/6;129SvEv mice over longer periods (13 to 18 weeks) using a high salt diet and L-NAME did not cause adverse fibrotic remodeling in the DTAs (Bellini et al, 2015;Spronck et al, 2019). Hence, again, genetic modifiers intrinsic to the 129SvEv strain appear to have a dominant role in attenuating aortic remodeling in multiple models of induced hypertension in…”

Structural and functional remodeling of the female Apoe−/− mouse aorta due to chronic cigarette smoke exposure

“…S1, E-H). Since we do not expect inhalation of cigarette smoke to influence axial tethering (27,57), collagen deposition (Fig. 4, E and F) presumably hindered the elastic fiber recoil, reducing the in vivo axial stretch (Fig.…”

Early Morphofunctional Changes in AngII-Infused Mice Contribute to Regional Onset of Aortic Aneurysm and Dissection

“…In literature, it has been shown that long-term infusion of AngII impairs the voltage-dependent contractions of the thoracic aorta [23]. Dysfunctional smooth muscle cell (SMC) contractility strongly correlates with maladaptive aortic remodeling and fibrosis [24]. Moreover, restoring smooth muscle contractility protects thoracic AD [25], suggesting that preserving contractile capacity may reduce mechanical stress-induced pathological events leading to AA and AD.…”