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1. Elastin haploinsufficiency in mice has divergent effects on arterial remodeling with aging depending on sex

   https://doi.org/10.1152/ajpheart.00517.2020  

   Hawes, Jie Z.; Cocciolone, Austin J.; Cui, Amy H.; Griffin, Diana B.; Staiculescu, Marius Catalin; Mecham, Robert P.; Wagenseil, Jessica E. (December 2020, American Journal of Physiology-Heart and Circulatory Physiology)

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   Elastin is a primary structural protein in the arterial wall that contributes to vascular mechanical properties and degrades with aging. Aging is associated with arterial stiffening and an increase in blood pressure. There is evidence that arterial aging follows different timelines with sex. Our objective was to investigate how elastin content affects arterial remodeling in male and female mice with aging. We used male and female wild-type ( Eln +/+ ) and elastin heterozygous ( Eln +/− ) mice at 6, 12, and 24 mo of age and measured their blood pressure and arterial morphology, wall structure, protein content, circumferential stress, stretch ratio, and stiffness. Two arteries were used with varying contents of elastin: the left common carotid and ascending aorta. We show that Eln +/− arteries start at a different homeostatic set point for circumferential wall stress, stretch, and material stiffness but show similar increases with aging to Eln +/+ mice. With aging, structural stiffness is greatly increased, while material stiffness and circumferential stress are only slightly increased, highlighting the importance of maintaining these homeostatic values. Circumferential stretch shows the smallest change with age and may be important for controlling cellular phenotype. Independent sex differences are mostly associated with males being larger than females; however, many of the measured factors show age × sex and/or genotype × sex interactions, indicating that males and females follow different cardiovascular remodeling timelines with aging and are differentially affected by reduced elastin content. NEW & NOTEWORTHY A comprehensive study on arterial mechanical behavior as a function of elastin content, aging, and sex in mice. Elastin haploinsufficient arteries start at a different homeostatic set point for mechanical parameters such as circumferential stress, stretch, and material stiffness. Structural stiffness of the arterial wall greatly increases with aging, as expected, but there are interactions between sex and aging for most of the mechanical parameters that are important to consider in future work. 

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2. Distinct time courses and mechanics of right ventricular hypertrophy and diastolic stiffening in a male rat model of pulmonary arterial hypertension

   https://doi.org/10.1152/ajpheart.00046.2021  

   Kwan, Ethan D.; Vélez-Rendón, Daniela; Zhang, Xiaoyan; Mu, Hao; Patel, Megh; Pursell, Erica; Stowe, Jennifer; Valdez-Jasso, Daniela (October 2021, American Journal of Physiology-Heart and Circulatory Physiology)

   Although pulmonary arterial hypertension (PAH) leads to right ventricle (RV) hypertrophy and structural remodeling, the relative contributions of changes in myocardial geometric and mechanical properties to systolic and diastolic chamber dysfunction and their time courses remain unknown. Using measurements of RV hemodynamic and morphological changes over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we discriminated the contributions of RV geometric remodeling and alterations of myocardial material properties to changes in systolic and diastolic chamber function. Significant and rapid RV hypertrophic wall thickening was sufficient to stabilize ejection fraction in response to increased pulmonary arterial pressure by week 4 without significant changes in systolic myofilament activation. After week 4, RV end-diastolic pressure increased significantly with no corresponding changes in end-diastolic volume. Significant RV diastolic chamber stiffening by week 5 was not explained by RV hypertrophy. Instead, model analysis showed that the increases in RV end-diastolic chamber stiffness were entirely attributable to increased resting myocardial material stiffness that was not associated with significant myocardial fibrosis or changes in myocardial collagen content or type. These findings suggest that whereas systolic volume in this model of RV pressure overload is stabilized by early RV hypertrophy, diastolic dilation is prevented by subsequent resting myocardial stiffening. NEW & NOTEWORTHY Using a novel combination of hemodynamic and morphological measurements over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we found that compensated systolic function was almost entirely explained by RV hypertrophy, but subsequently altered RV end-diastolic mechanics were primarily explained by passive myocardial stiffening that was not associated with significant collagen extracellular matrix accumulation. 

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3. Collagen Fibril Abnormalities in Human and Mice Abdominal Aortic Aneurysm

   Jones, B.; Tonniges, J. R.; Debsk, A.i; Albert, B.; Yeung, D. A.; Gadde, N.; Mahajan, A.; Sharma, N.; Calomeni, E. P.; Go, M.; et al (August 2020, Biomedical Engineering Society 2020 Annual Meeting)

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   Introduction: Vascular diseases like abdominal aortic aneurysms (AAA) are characterized by a drastic remodeling of the vessel wall, accompanied with changes in the elastin and collagen content. At the macromolecular level, the elastin fibers in AAA have been reported to undergo significant structural alterations. While the undulations (waviness) of the collagen fibers is also reduced in AAA, very little is understood about changes in the collagen fibril at the sub-fiber level in AAA as well as in other vascular pathologies. Materials and Methods: In this study we investigated structural changes in collagen fibrils in human AAA tissue extracted at the time of vascular surgery and in aorta extracted from angiotensin II (AngII) infused ApoE−/− mouse model of AAA. Collagen fibril structure was examined using transmission electron microscopy and atomic force microscopy. Images were analyzed to ascertain length and depth of D-periodicity, fibril diameter and fibril curvature. Tissues were also stained using collagen hybridizing peptide (CHP) and analyzed using fluorescent microscopy and second harmonic generation (SHG) microscopy to locate regions of healthy and degraded collagen. Results: Abnormal collagen fibrils with compromised D-periodic banding were observed in the excised human tissue and in remodeled regions of AAA in AngII infused mice (Figure 1). These abnormal fibrils were characterized by statistically significant reduction in depths of D-periods and an increased curvature of collagen fibrils. These features were more pronounced in human AAA as compared to murine samples. Additionally, regions of abnormal collagen were located within the remodeled areas of AAA tissue and were distinct from healthy collagen regions as ascertained using CHP staining and SHG (Figure 1). Thoracic aorta from Ang II-infused mice, abdominal aorta from saline-infused mice, and abdominal aorta from non-AAA human controls did not contain abnormal collagen fibrils. Conclusions: The structural alterations in abnormal collagen fibrils appear similar to those reported for collagen fibrils subjected to mechanical overload or chronic inflammation in other tissues. Detection of abnormal collagen could be utilized to better understand the functional properties of the underlying extracellular matrix in vascular as well as other pathologies. 

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4. A Mathematical Model of Maladaptive Inward Eutrophic Remodeling of Muscular Arteries in Hypertension

   https://doi.org/10.1115/1.4055109  

   Rachev, Alexander; Shazly, Tarek (January 2023, Journal of Biomechanical Engineering)

   Abstract We propose a relatively simple two-dimensional mathematical model for maladaptive inward remodeling of resistive arteries in hypertension in terms of vascular solid mechanics. The main premises are: (i) maladaptive inward remodeling manifests as a reduced increase in the arterial mass compared to the case of adaptive remodeling under equivalent hypertensive pressures and (ii) the pressure-induced circumferential stress in the arterial wall is restored to its basal target value as happens in the case of adaptive remodeling. The rationale for these assumptions is the experimental findings that elevated tone in association with sustained hypertensive pressure down-regulate the normal differentiation of vascular smooth muscle cells from contractile to synthetic phenotype and the data for the calculated hoop stress before and after completion of remodeling. Results from illustrative simulations show that as the hypertensive pressure increases, remodeling causes a nonmonotonic variation of arterial mass, a decrease in inner arterial diameter, and an increase in wall thickness. These findings and the model prediction that inward eutrophic remodeling is preceded by inward hypertrophic remodeling are supported by published observations. Limitations and perspectives for refining the mathematical model are discussed. 

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5. MICROMECHANICAL MODEL OF MECHANOSENSITIVE COLLAGEN TISSUES

   Younger, Kalyn G; Cortes, William; Reich, Daniel H; Nguyen, Thao D (June 2022, Summer Biomechanics, Bioengineering and Biotransport Conference)

   The mechanical behavior of soft collagenous tissues is largely influenced by the reinforcing collagen fiber microstructure. The anisotropic collagen microstructure can remodel in response to changes in mechanical loading, which can dramatically alter the mechanical properties of the tissues and the mechanical environment of the resident cells. It is important to study the remodeling mechanisms of collagen tissues to understand the pathophysiology of various connective tissue diseases. We hypothesize that the collagen structure actively changes in response to mechanical stimuli through concurrent processes of collagen deposition and degradation and that the rates of these processes are altered by collagen mechanochemistry, mechanosensitive collagen production, and cellular contraction. In prior studies, we developed micromechanical models of collagen tissues to investigate the role of collagen mechanochemistry and mechanosensitive collagen production in remodeling the collagen fiber structure and tissue growth.[1,2] We found that stress inhibition of enzymatic degradation and stimulation of collagen production can explain many phenomena, including remodeling the anisotropic collagen structure along the directions of the maximum principal stress and the development of stress homeostasis. The goal of this study is to investigate the effect of mechanical loading on the active behavior of the cells. Our approach uses a model 3D microtissue systems, self-assembled on a magnetically actuated two-pillar system (µTUG), to investigate these cell-collagen interactions and effects of mechanical loading. The micropillar support allows for measurement of the active cellular contraction, while the magnetic tweezer allows for mechanical testing of the microtissue under a controlled stress rate. Digital image analysis is applied to measure the local two-dimensional (2D) strain field. To analyze the mechanical measurements for mechanical properties of the collagen structure and active behavior of the cells, we developed a micromechanical model for the mechanical behavior of the microtissue. The micromechanical model includes the elastic behavior of the anisotropic collagen structure and the anisotropic active behavior of the cells. To describe mechanosensitive cellular contraction, we assume concurrent polymerization/depolymerization of actin filaments, where the polymerization rate increases with the fiber stress. In this paper, we will briefly summarize the model and describe an initial model validation by comparing to µTUG experiments measuring the stress-strain behavior of the microtissue to load-unload tests. 

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