Compromised mechanical homeostasis in arterial aging and associated cardiovascular consequences

Abstract

Aging leads to central artery stiffening and associated hemodynamic sequelae. Because healthy arteries exhibit differential geometry, composition, and mechanical behaviors along the central vasculature, we sought to determine whether wall structure and mechanical function differ across five vascular regions-the ascending and descending thoracic aorta, suprarenal and infrarenal abdominal aorta, and common carotid artery-in 20 versus 100-week-old male wild-type mice. Notwithstanding generally consistent changes across these regions, including a marked thickening of the arterial wall, diminished in vivo axial stretch, and loss of elastic energy storage capacity, the degree of changes tended to be slightly greater in abdominal than in thoracic or carotid vessels. Likely due to the long half-life of vascular elastin, most mechanical changes in the arterial wall resulted largely from a distributed increase in collagen, including thicker fibers in the media, and localized increases in glycosaminoglycans. Changes within the central arteries associated with significant increases in central pulse pressure and adverse changes in the left ventricle, including increased cardiac mass and decreased diastolic function. Given the similar half-life of vascular elastin in mice and humans but very different life-spans, there are important differences in the aging of central vessels across these species. Nevertheless, the common finding of aberrant matrix remodeling contributing to a compromised mechanical homeostasis suggests that studies of central artery aging in the mouse can provide insight into mechanisms and treatment strategies for the many adverse effects of vascular aging in humans.

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

“…In humans, a conspicuous change is diffuse elastic fiber fragmentation with an associated modest uniform dilatation and stiffening of the wall [ 47 – 49 ]. Fig D in S1 Supporting Information also shows simulated effects of an aging-related uniform loss of 30% of the elastic fibers relative to our baseline aortic model, which reflects well the general empirical observations, including a (irreversible) reduction in elastic energy storage [ 50 ]. Finally, the bottom panels in Fig D in S1 Supporting Information show aortic remodeling in response to a sustained elevation of pressure combined with such aging.…”

“…Again, the effects of aging on the vasculature are manifold, including endothelial dysfunction, smooth muscle phenotypic modulation or apoptosis, extracellular matrix remodeling, and inflammation [ 66 , 67 ]. Our model of aging focused on the diffuse loss of elastic fiber integrity, as in human though not natural murine aging [ 50 ]. Consistent with observations in clinical and animal model studies, our in silico simulations yielded an aortic wall that remodeled in hypertension primarily via an increase in wall thickness and in aging primarily via an increase in caliber, both uniformly and both consistent with an initial mechano-adaptative response (i.e., in the absence of intramural cell dysfunction or inflammation).…”

Combining in vivo and in vitro biomechanical data reveals key roles of perivascular tethering in central artery function

“…The former supports the use of a “Small on Large” theory [ 24 ] to compute material stiffness for use in fluid-solid-interaction simulations of the hemodynamics. Related to the latter, it was surprising that the in vivo value of stress tended to decrease with decreasing caliber, which tends to associate with less elastin and more smooth muscle [ 16 , 35 ]. It would be useful to quantify possible regional differences in basal tone and how such differences could affect local stresses, noting that basal tone, if present, would be expected to be low in exercise and exertion to reduce the workload of the heart, consistent with increased flow-induced wall shear stress promoting endothelial cell nitric oxide production.…”

“…Similarly, there is a pressing need for complementary hemodynamic simulations given the difficulty of measuring cyclic pressures locally throughout the murine vasculature [ 38 ], which can vary from region to region [ 39 ]. Finally, we did not include histological data that show regional differences in composition since such results are available elsewhere [ 16 , 35 , 40 ]. Although it is not possible to know precisely whether adventitial collagen has been inadvertently removed when eliminating loose perivascular tissue, results obtained by different investigators in our laboratory have yielded similar values of wall thickness and medial:adventitial ratios.…”

Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome

“…Because biomechanical mechanisms of dissection are very different from those of aneurysmal dilatation(Bellini et al 2014;Ferruzzi et al 2018b), there remains a need to evaluate the mechanics further in these multiple mouse models, particularly in cases of induced hypertension and in older mice. Indeed, differential aortic aging in mice and humans may contribute to inherent differences between mouse models of thoracic aortopathy and actual human disease.…”