Sirtuin-1 (SirT1), a nicotinamide adenine dinucleotide(+)-dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses; however, the role of ...endogenous SirT1 in the vasculature has not been fully elucidated. Our goal was to evaluate the role of vascular smooth muscle SirT1 in the physiological response of the aortic wall to angiotensin II, a potent hypertrophic, oxidant, and inflammatory stimulus.
Mice lacking SirT1 in vascular smooth muscle (ie, smooth muscle SirT1 knockout) had drastically high mortality (70%) caused by aortic dissection after angiotensin II infusion (1 mg/kg per day) but not after an equipotent dose of norepinephrine, despite comparable blood pressure increases. Smooth muscle SirT1 knockout mice did not show any abnormal aortic morphology or blood pressure compared with wild-type littermates. Nonetheless, in response to angiotensin II, aortas from smooth muscle SirT1 knockout mice had severely disorganized elastic lamellae with frequent elastin breaks, increased oxidant production, and aortic stiffness compared with angiotensin II-treated wild-type mice. Matrix metalloproteinase expression and activity were increased in the aortas of angiotensin II-treated smooth muscle SirT1 knockout mice and were prevented in mice overexpressing SirT1 in vascular smooth muscle or with use of the oxidant scavenger tempol.
Endogenous SirT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli, at least in part, by suppressing oxidant-induced matrix metalloproteinase activity. SirT1 activators could potentially be a novel therapeutic approach to prevent aortic dissection and rupture in patients at risk, such as those with hypertension or genetic disorders, such as Marfan's syndrome.
Metabolic syndrome increases the risk of cardiovascular diseases. Arteries gradually stiffen with aging; however, it can be worsened by the presence of conditions associated with metabolic syndrome. ...In this study, we investigated the combined effects of diet-induced metabolic syndrome and aging on the biomechanical properties of mouse common carotid arteries (CCA). Male mice at 2 months of age were fed a normal or a high fat and high sucrose (HFHS) diet for 2 (young group), 8 (adult group) and 18-20 (old group) months. CCAs were excised and subjected to
biaxial inflation-extension tests and the Cauchy stress-stretch relationships were determined in both the circumferential and longitudinal directions. The elastic energy storage of CCAs was obtained using a four-fiber family constitutive model, while the material stiffness in the circumferential and longitudinal directions was computed. Our study showed that aging is a dominant factor affecting arterial remodeling in the adult and old mice, to a similar extent, with stiffening manifested with a significantly reduced capability of energy storage by ∼50% (
< 0.05) and decreases in material stiffness and stress (
< 0.05), regardless of diet. On the other hand, high fat high sucrose diet resulted in an accelerated arterial remodeling in the young group at pre-diabetic stage by affecting the circumferential material stiffness and stress (
< 0.05), which was eventually overshadowed by aging progression. These findings have important implications on the effects of metabolic syndrome on elastic arteries in the younger populations.
Inter-fiber crosslinks within the extracellular matrix (ECM) play important roles in determining the mechanical properties of the fibrous network. Discrete fiber network (DFN) models have been used ...to study fibrous biological material, however the contribution of inter-fiber crosslinks to the mechanics of the ECM network is not well understood. In this study, a DFN model of arterial elastin network was developed based on measured structural features to study the contribution of inter-fiber crosslinking properties and density to the mechanics and fiber kinematics of the network. The DFN was generated by randomly placing line segments into a given domain following a fiber orientation distribution function obtained from multiphoton microscopy until a desired fiber areal fraction was reached. Intersections between the line segments were treated as crosslinks. The generated DFN model was then incorporated into an ABAQUS finite element model to simulate the network under equi- and nonequi-biaxial deformation. The inter-fiber crosslinks were modeled using connector elements with either zero (pin joint) or infinite (weld joint) rotational stiffness. Furthermore, inter-fiber crosslinking density was systematically reduced and its effect on both network- and fiber-level mechanics was studied. The DFN model showed good fitting and predicting capabilities of the stress-strain behavior of the elastin network. While the pin and weld joints do not seem to have noticeable effect on the network stress-strain behavior, the crosslinking properties can affect the local fiber mechanics and kinematics. Overall, our study suggests that inter-fiber crosslinking properties are important to the multiscale mechanics and fiber kinematics of the ECM network.
Collagen type I scaffolds are commonly used due to its abundance, biocompatibility, and ubiquity. Most applications require the scaffolds to operate under mechanical stresses. Therefore understanding ...and being able to control the structural-functional integrity of collagen scaffolds becomes crucial. Using a combined experimental and modeling approach, we studied the structure and function of Type I collagen gel with the effects of spatial fiber alignment and crosslinking. Aligned collagen scaffolds were created through the flow of magnetic particles enmeshed in collagen fibrils to mimic the anisotropy seen in native tissue. Inter- and intra- molecular crosslinking was modified chemically with Genipin to further improve the stiffness of collagen scaffolds. The anisotropic mechanical properties of collagen scaffolds were characterized using a planar biaxial tensile tester and parallel plate rheometer. The tangent stiffness from biaxial tensile test is two to three orders of magnitude higher than the storage moduli from rheological measurements. The biphasic nature of collagen gel was discussed and used to explain the mechanical behavior of collagen scaffolds under different types of mechanical tests. An anisotropic hyperelastic constitutive model was used to capture the characteristics of the stress-strain behavior exhibited by collagen scaffolds.
Aortic aneurysm is an important clinical condition characterized by common structural changes such as the degradation of elastin, loss of smooth muscle cells, and increased deposition of fibrillary ...collagen. With the goal of investigating the relationship between the mechanical behavior and the structural/biochemical composition of an artery, this study used a simple chemical degradation model of aneurysm and investigated the progressive changes in mechanical properties. Porcine thoracic aortas were digested in a mild solution of purified elastase (5 U/mL) for 6, 12, 24, 48, and 96 h. Initial size measurements show that disruption of the elastin structure leads to increased artery dilation in the absence of periodic loading. The mechanical properties of the digested arteries, measured with a biaxial tensile testing device, progress through four distinct stages termed (1) initial-softening, (2) elastomer-like, (3) extensible-but-stiff, and (4) collagen-scaffold-like. While stages 1, 3, and 4 are expected as a result of elastin degradation, the S-shaped stress versus strain behavior of the aorta resulting from enzyme digestion has not been reported previously. Our results suggest that gradual changes in the structure of elastin in the artery can lead to a progression through different mechanical properties and thus reveal the potential existence of an important transition stage that could contribute to artery dilation during aneurysm formation.
The mechanical properties of elastin network from bovine thoracic aorta under biaxial tensile loading were studied both experimentally and theoretically. Histology and scanning electron microscopy ...were performed to verify the removal of cells, collagen, and other extracellular matrix components. Equi- and nonequi-biaxial tests were performed to study the effect of different loading conditions on the stress-strain responses of the elastin network. The mechanical properties of different elastin sections along the thoracic aorta were examined and studied to understand the anisotropy of elastin along the whole artery. Biaxial tensile test data comparing elastin vs. intact aorta showed that elastin is mainly responsible for the linear elastic response of the arterial wall at lower strains. Experimental results revealed that elastin network possesses significant anisotropic mechanical properties with the circumferential direction being stiffer than the longitudinal direction. The mechanical properties of elastin vary significantly along the thoracic aorta, with the thin section appearing to have the highest tangent modulus. Biological assay results indicate that elastin content is about the same along the thoracic aorta. The mechanical behavior of elastin network was well captured by the eight-chain statistical mechanics based microstructural model. Material parameters obtained from the equi-biaxial test were able to predict the stress-strain responses of elastin network under arbitrary nonequi-biaxial loading conditions. Also, by varying material parameters in the model, the changes in microstructure such as elastin fiber orientation and cross-linking density on the macroscopic mechanical properties of elastin network were discussed.
Ligamentum nuchae
is a highly elastic tissue commonly used to study the structure and mechanics of elastin. This study combines imaging, mechanical testing, and constitutive modeling to examine the ...structural organization of elastic and collagen fibers and their contributions to the nonlinear stress–strain behavior of the tissue. Rectangular samples of bovine
ligamentum nuchae
cut in both longitudinal and transverse directions were tested in uniaxial tension. Purified elastin samples were also obtained and tested. It was observed that the stress–stretch response of purified elastin tissue follows a similar curve as the intact tissue initially, but the intact tissue shows a significant stiffening behavior for stretches above 1.29 with collagen engagement. Multiphoton and histology images confirm the elastin-dominated bulk of
ligamentum nuchae
interspersed with small bundles of collagen fibrils and sporadic collagen-rich regions with cellular components and ground substance. A transversely isotropic constitutive model that considers the longitudinal organization of elastic and collagen fibers was developed to describe the mechanical behavior of both intact and purified elastin tissue under uniaxial tension. These findings shed light on the unique structural and mechanical roles of elastic and collagen fibers in tissue mechanics and may aid in future use of
ligamentum nuchae
in tissue grafting.
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