Excessive Adventitial Remodeling Leads to Early Aortic Maladaptation in Angiotensin-Induced Hypertension

Abstract

The primary function of central arteries is to store elastic energy during systole and to use it to sustain blood flow during diastole. Arterial stiffening compromises this normal mechanical function and adversely affects end organs such as the brain, heart, and kidneys. Using an angiotensin-II infusion model of hypertension in wild-type mice, we show that the thoracic aorta exhibits a dramatic loss of energy storage within two weeks that persists for at least four weeks. This diminished mechanical functionality results from increased structural stiffening due to an excessive accumulation of adventitial collagen, not a change in the intrinsic stiffness of the wall. A detailed analysis of the transmural biaxial wall stress suggests that the exuberant production of collagen results more from an inflammatory response than a mechano-adaptation, hence reinforcing the need to control inflammation, not just blood pressure. Although most clinical assessments of arterial stiffening focus on intimal-medial thickening, these results suggest a need to measure and control the highly active and important adventitia.

Modeling mechano-driven and immuno-mediated aortic maladaptation in hypertension

“…Valentín et al 2009). Here, we briefly describe our method for parameter estimation based largely on experimental findings in Wu et al (2014) and Bersi et al (2016) for a particular mouse model of hypertension for which information is available on the time course of changes in blood pressure, wall composition, and material properties with known roles of inflammatory cells.…”

“…Hence, using information from Tables S1 and S2 in Bersi et al (2016), we recreated the biaxial data and determined best-fit values for the original (labeled Sham in Bersi et al (2016)) and evolved ( 4wk Ang II ) biaxial stress-stretch data. Because of the observed maladaptive evolution in Bersi et al (2016), we let the elastic material parameters for collagen and smooth muscle (which turnover continuously) potentially evolve, whereby we determined: material parameters in the neoHookean (constant) and Fung-type (original/evolved) relations for elastin, collagen, and circumferential smooth muscle as well as appropriate deposition streches for elastin (constant) as well as collagen and smooth muscle (original/evolved). Because the previous constrained mixture model yields a mass-based rule-of-mixture expression for stresses for transient elastic (biaxial) responses, we also recreated (original and evolved) histological fractions from Figure 3 in Bersi et al (2016) consistent, again, with predicted relations for our constrained mixture model for G&R (cf.…”

“…The associated morphological consequences are, a → ε 1/3 a o and h → γε 1/3 h o , where ε is the fold-change in blood flow and γ is the fold-change in blood pressure, with a subscript o denoting an original homeostatic value (Humphrey 2008a). Assuming preserved cardiac output ( ε ≃ 1), findings in Bersi et al (2016) reveal that γ ≃ 1.36 over two-to-four weeks of angiotensin-II induced hypertension in normal adult male mice C57BL/6J, but h / h o > 2.5 in the descending thoracic aorta over this same period. That is, thickening was grossly excessive relative to the mechanical stimulus.…”

“…These advances have been driven by increasingly sophisticated theoretical concepts and detailed experimental findings. Regarding the latter, recent data reveal a dramatic influence of inflammation-mediated adventitial fibrosis in multiple murine models of induced hypertension (Wu et al 2014, 2016), which has been shown to be maladaptive from a mechanobiological perspective (Bersi et al 2016). In particular, mechano-adaptation of an artery can often be defined in terms of changes in luminal radius a and wall thickness h that restore toward normal both the mean flow-induced wall shear stress ( τ w = 4 μQ /( πa 3 ), where Q is the blood flowrate and μ is the blood viscosity) and the mean pressure-induced circumferential wall stress ( σ θθ = Pa / h , where P is transmural blood pressure).…”

Adventures in the Adventitia

“…However, there is a growing body of knowledge that points to the adventitia as a significant and perhaps even the principal contributor to pathological hypertensive remodeling. In this issue of Hypertension, Bersi et al 2 provide convincing evidence that when it comes to stiffness and stress, we ought to take a closer look at the outer aspect of the arterial wall.…”