The stiffness and structural integrity of the arterial wall depends primarily on the organization of the extracellular matrix and the cells that fashion and maintain this matrix. Fundamental to the latter is a delicate balance in the continuous production and removal of structural constituents and the mechanical state in which such turnover occurs. Perturbations in this balance due to genetic mutations, altered hemodynamics, or pathological processes result in diverse vascular phenotypes, many of which have yet to be well characterized biomechanically. In this paper, we emphasize the particular need to understand regional variations in the biaxial biomechanical properties of central arteries in health and disease and, in addition, the need for standardization in the associated biaxial testing and quantification. As an example of possible experimental methods, we summarize testing protocols that have evolved in our laboratory over the past 8 years. Moreover, we note advantages of a four fiber family stress – stretch relation for quantifying passive biaxial behaviors, the use of stored energy as a convenient scalar metric of the associated material stiffness, and the utility of appropriate linearizations of the nonlinear, anisotropic relations both for purposes of comparison across laboratories and to inform computational fluid-solid-interaction models. We conclude that, notwithstanding prior advances, there remain many opportunities to advance our understanding of arterial mechanics and mechanobiology, particularly via the diverse genetic, pharmacological, and surgical models that are, or soon will be, available in the mouse.

The embryonic lineage of intramural cells, microstructural organization of the extracellular matrix, local luminal and wall geometry, and haemodynamic loads vary along the length of the aorta. Yet, it remains unclear why certain diseases manifest differentially along the aorta. Toward this end, myriad animal models provide insight into diverse disease conditions-including fibrosis, aneurysm and dissection-but inherent differences across models impede general interpretations. We examined region-specific cellular, matrix, and biomechanical changes in a single experimental model of hypertension and atherosclerosis, which commonly coexist. Our findings suggest that (i) intramural cells within the ascending aorta are unable to maintain the intrinsic material stiffness of the wall, which ultimately drives aneurysmal dilatation, (ii) a mechanical stress-initiated, inflammation-driven remodelling within the descending aorta results in excessive fibrosis, and (iii) a transient loss of adventitial collagen within the suprarenal aorta contributes to dissection propensity. Smooth muscle contractility helps to control wall stress in the infrarenal aorta, which maintains mechanical properties near homeostatic levels despite elevated blood pressure. This early mechanoadaptation of the infrarenal aorta does not preclude subsequent acceleration of neointimal formation, however. Because region-specific conditions may be interdependent, as, for example, diffuse central arterial stiffening can increase cyclic haemodynamic loads on an aneurysm that is developing proximally, there is a clear need for more systematic assessments of aortic disease progression, not simply a singular focus on a particular region or condition.

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.

Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in aging, hypertension, and related conditions. Elastic fibers consist of an elastin core and multiple glycoproteins; hence defects in any of these constituents can adversely affect arterial wall mechanics. In this paper, we focus on mechanical consequences of the loss of fibulin-5, an elastin-associated glycoprotein involved in elastogenesis. Specifically, we compared the biaxial mechanical properties of five central arteries-the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and common carotid artery-from male and female wild-type and fibulin-5 deficient mice. Results revealed that, independent of sex, all five regions in the fibulin-5 deficient mice manifested a marked increase in structural stiffness but also a marked decrease in elastic energy storage and typically an increase in energy dissipation, with all differences being most dramatic in the ascending and abdominal aortas. Given that the primary function of large arteries is to store elastic energy during systole and to use this energy during diastole to work on the blood, fibulin-5 deficiency results in a widespread diminishment of central artery function that can have significant effects on hemodynamics and cardiac function.

Thoracic aortic aneurysms are life-threatening lesions that afflict young and old individuals alike. They frequently associate with genetic mutations and are characterized by reduced elastic fibre integrity, dysfunctional smooth muscle cells, improperly remodelled collagen and pooled mucoid material. There is a pressing need to understand better the compromised structural integrity of the aorta that results from these genetic mutations and renders the wall vulnerable to dilatation, dissection or rupture. In this paper, we compare the biaxial mechanical properties of the ascending aorta from 10 murine models: wild-type controls, acute elastase-treated, and eight models with genetic mutations affecting extracellular matrix proteins, transmembrane receptors, cytoskeletal proteins, or intracellular signalling molecules. Collectively, our data for these diverse mouse models suggest that reduced mechanical functionality, as indicated by a decreased elastic energy storage capability or reduced distensibility, does not predispose to aneurysms. Rather, despite normal or lower than normal circumferential and axial wall stresses, it appears that intramural cells in the ascending aorta of mice prone to aneurysms are unable to maintain or restore the intrinsic circumferential material stiffness, which may render the wall biomechanically vulnerable to continued dilatation and possible rupture. This finding is consistent with an underlying dysfunctional mechanosensing or mechanoregulation of the extracellular matrix, which normally endows the wall with both appropriate compliance and sufficient strength.

Many vascular disorders, including aortic aneurysms and dissections, are characterized by localized changes in wall composition and structure. Notwithstanding the importance of histopathologic changes that occur at the microstructural level, macroscopic manifestations ultimately dictate the mechanical functionality and structural integrity of the aortic wall. Understanding structure-function relationships locally is thus critical for gaining increased insight into conditions that render a vessel susceptible to disease or failure. Given the scarcity of human data, mouse models are increasingly useful in this regard. In this paper, we present a novel inverse characterization of regional, nonlinear, anisotropic properties of the murine aorta. Full-field biaxial data are collected using a panoramic-digital image correlation (p-DIC) system. An inverse method, based on the principle of virtual power (PVP), is used to estimate values of material parameters regionally for a microstructurally motivated constitutive relation. We validate our experimental-computational approach by comparing results to those from standard biaxial testing. The results for the nondiseased suprarenal abdominal aorta from apolipoprotein-E null mice reveal material heterogeneities, with significant differences between dorsal and ventral as well as between proximal and distal locations, which may arise in part due to differential perivascular support and localized branches. Overall results were validated for both a membrane and a thick-wall model that delineated medial and adventitial properties. Whereas full-field characterization can be useful in the study of normal arteries, we submit that it will be particularly useful for studying complex lesions such as aneurysms, which can now be pursued with confidence given the present validation.

We recently developed an approach to characterize local nonlinear, anisotropic mechanical properties of murine arteries by combining biaxial extension-distension testing, panoramic digital image correlation (pDIC), and an inverse method based on the principle of virtual power. This experimental-computational approach was illustrated for the normal murine abdominal aorta assuming uniform wall thickness. Here, however, we extend our prior approach by adding an optical coherence tomography (OCT) imaging system that permits local reconstructions of wall thickness. This multi-modality approach is then used to characterize spatial variations of material and structural properties in ascending thoracic aortic aneurysms (aTAA) from two genetically modified mouse models (fibrillin-1 and fibulin-4 deficient) and to compare them with those from angiotensin-II infused apolipoprotein-E deficient and wild-type control aortas. Local values of stored elastic energy and biaxial material stiffness, computed from spatial distributions of the bestfit material parameters, varied significantly with circumferential position (inner vs. outer curvature, ventral vs. dorsal sides) across genotypes and treatments. Importantly, these data reveal an inverse relationship between material stiffness and wall thickness that underlies a general linear relationship between stiffness and wall stress across aTAAs. OCT images also revealed sites of advanced medial degeneration, which were captured by the inverse material characterization. Quantification of histological data further provided high resolution local correlations amongst multiple mechanical metrics and wall microstructure. This is the first time that such structural defects and local properties have been characterized mechanically, which can better inform computational models of aortopathy that seek to predict where dissection or rupture may initiate.

Many surgical interventions for cardiovascular disease are limited by the availability of autologous vessels or suboptimal performance of prosthetic materials. Tissue engineered vascular grafts show significant promise, but have yet to achieve clinical efficacy in small caliber (<5 mm) arterial applications. We previously designed cell-free elastomeric grafts containing solvent casted, particulate leached poly(glycerol sebacate) (PGS) that degraded rapidly and promoted neoartery development in a rat model over 3 months. Building on this success but motivated by the need to improve fabrication scale-up potential, we developed a novel method for electrospinning smaller grafts composed of a PGS microfibrous core enveloped by a thin poly(ε-caprolactone) (PCL) outer sheath. Electrospun PGS-PCL composites were implanted as infrarenal aortic interposition grafts in mice and remained patent up to the 12 month endpoint without thrombosis or stenosis. Many grafts experienced a progressive luminal enlargement up to 6 months, however, due largely to degradation of PGS without interstitial replacement by neotissue. Lack of rupture over 12 months confirmed sufficient long-term strength, due primarily to the persistent PCL sheath. Immunohistochemistry further revealed organized contractile smooth muscle cells and neotissue in the inner region of the graft, but a macrophage-driven inflammatory response to the residual polymer in the outer region of the graft that persisted up to 12 months. Overall, the improved surgical handling, long-term functional efficacy, and strength of this new graft strategy are promising, and straightforward modifications of the PGS-core should hasten cellular infiltration and associated neotissue development and thereby lead to improved small vessel replacements.