Mechanisms of Vascular Remodeling in Hypertension

Abstract

Hypertension is both a cause and a consequence of central artery stiffening, which in turn is an initiator and indicator of myriad disease conditions and thus all-cause mortality. Such stiffening results from a remodeling of the arterial wall that is driven by mechanical stimuli and mediated by inflammatory signals, which together lead to differential gene expression and concomitant changes in extracellular matrix composition and organization. This review focuses on biomechanical mechanisms by which central arteries remodel in hypertension within the context of homeostasis-what promotes it, what prevents it. It is suggested that the vasoactive capacity of the wall and inflammatory burden strongly influence the ability of homeostatic mechanisms to adapt the arterial wall to high blood pressure or not. Maladaptation, often reflected by inflammation-driven adventitial fibrosis, not just excessive intimal-medial thickening, significantly diminishes central artery function and disturbs hemodynamics, ultimately compromising end organ perfusion and thus driving the associated morbidity and mortality. It is thus suggested that there is a need for increased attention to controlling both smooth muscle phenotype and inflammation in hypertensive remodeling of central arteries, with future studies of the often adaptive response of medium-sized muscular arteries promising to provide additional guidance.

Keywords: blood pressure; high blood pressure; homeostasis; hypertension; inflammation; matrix turnover; stress.

Graphical Abstract

Figure 1.

(a) Schematic drawing showing 4 components of the mechanical stress and the areas on which they act: flow-induced wall shear stress τ_w ~ 5 Pa and pressure-induced radial σ_r ~ −6 kPa, circumferential σ_θ ~ 150 kPa, and axial σ_z ~ 150 kPa wall stress, with these values representative of the mouse descending thoracic aorta shown in a histological cross-section (note: 1 Pascal, Pa, is 1 Newton per meter squared). Although these values represent well the mean values, different values of the intramural stress exist in the media (higher) and adventitia (lower), suggesting different levels of mechano-sensitivity for all 3 primary cell types: endothelial, smooth muscle, and fibroblasts. (b) Representative biomechanical data emphasizing that luminal radius a (top row) and wall thickness h (bottom row) change acutely in response to both increased smooth muscle cell contractility (left) and distending pressure (right), both of which thereby govern mean circumferential wall stress, as, for example, via the Laplace equation, ${\sigma }_{\theta }=Pa(P,C)/h(P,C)$, where P is pressure and C is contractility. Data courtesy of Dr Sae-Il Murtada (author’s lab). Abbreviation: PE, phenylephrine.

Figure 2.

Schema of a negative feedback system characteristic of mechanical homeostasis in arteries, defined by the mechanical stimuli that give rise to the mechanical state (e.g., values of mechanical stress) that are sensed by the cells (e.g., via integrins), with the perceived state compared with homeostatic set-points (target values) to drive possible cell and tissue turnover at stress-modulated rates, determined in part by system gains (sensitivities). Inflammation can promote or prevent homeostasis, depending on the inflammatory burden, the former usually via acute and the latter via chronic inflammation. Note: min{deviations} is the homeostatic process by which the deviations from set points are resolved.

Figure 3.

Time-course of restorative (homeostatic) responses of the mouse infrarenal abdominal aorta to 28 days of angiotensin II-induced hypertension (top left, systolic pressure changes over 4 weeks, noting that mean and diastolic pressures increased as well). Shown too are normalized (to values at day 0, prior to inducing hypertension) values of luminal radius (top, middle) and wall thickness (top, right); in contrast to the acute contraction- and pressure-dependent changes geometry in Figure 1b, these changes are entrenched due to remodeling. Shown, too, are evolving values of circumferential wall stress (bottom, left) and material stiffness (bottom, middle) as well as elastic energy storage (bottom, right). Note that wall stress and stiffness first increase with increasing pressure, then tend back toward (but not to) the homeostatic values (horizontal dotted line). This partial restoration was due in large part to the increase in wall thickness, but also a decrease in axial stretch (not shown). Note that basal tone (not included) would bring both stress and stiffness even closer to original values. Data replotted from Bersi et al.

Figure 4.

Schema representing degrees of deviation in the perceived state from the homeostatic set-point (cf. Figure 2). When the deviation is modest, a mechanically homeostatic (stress) response can be sufficient; when the deviation is slightly greater, a homeostasis-promoting para-inflammatory response can yield a stable state, often adaptive. If the degree of deviation in the perceived state is far from the homeostatic set-point, homeostasis-preventing inflammation may result in maladaptation. Motivated by concepts presented by Chovatiya and Medzhitov.

Figure 5.

Schema of the differential responses of large (elastic), medium-sized (muscular), and small (arterioles) arteries to a sustained increase in blood pressure (hypertension, HTN). All 3 types of vessels tend to thicken in an attempt to restore wall stress back toward normal (cf. Figure 3), yet the luminal response is very different, likely reflecting differential smooth muscle phenotypes. Interestingly, dilatation of the elastic arteries is not ideal, but it can help reduce the increased pulse wave velocity that results from structural stiffening; similarly, luminal encroachment in the arterioles is not ideal, but it may help attenuate the penetration of pulse pressure waves into the microcirculation.^,