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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. 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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3. Aortic stiffness is lower when PVAT is included: a novel ex vivo mechanics study

   https://doi.org/10.1152/ajpheart.00574.2021  

   Tuttle, Tyler; Darios, Emma; Watts, Stephanie W.; Roccabianca, Sara (June 2022, American Journal of Physiology-Heart and Circulatory Physiology)

   Perivascular adipose tissue (PVAT) is increasingly recognized as an essential layer of the functional vasculature, being responsible for producing vasoactive substances and assisting arterial stress relaxation. Here, we test the hypothesis that PVAT reduces aortic stiffness. Our model was the thoracic aorta of the male Sprague–Dawley rat. Uniaxial mechanical tests for three groups of tissue were performed: aorta with PVAT attached (+PVAT) or removed (−PVAT), and isolated PVAT (PVAT only). The output of the mechanical test is reported in the form of a Cauchy stress-stretch curve. This work presents a novel, physiologically relevant approach to measure mechanical stiffness ex vivo in isolated PVAT. Low-stress stiffness ( E 0 ), high-stress stiffness ( E 1 ), and the stress corresponding to a stretch of 1.2 (σ 1.2 ) were measured as metrics of distensibility. The low-stress stiffness was largest in the −PVAT samples and smallest in PVAT only samples. Both the high-stress stiffness and the stress at 1.2 stretch were significantly higher in −PVAT samples when compared with +PVAT samples. Taken together, these results suggest that −PVAT samples are stiffer (less distensible) both at low stress (not significant) as well as at high stress (significant) when compared with +PVAT samples. These conclusions are supported by the results of the continuum mechanics material model that we also used to interpret the same experimental data. Thus, tissue stiffness is significantly lower when considering PVAT as part of the aortic wall. As such, PVAT should be considered as a target for improving vascular function in diseases with elevated aortic stiffness, including hypertension. NEW & NOTEWORTHY We introduce a novel and physiologically relevant way of measuring perivascular adipose tissue (PVAT) mechanical stiffness which shows that PVAT’s low, yet measurable, stiffness is linearly correlated with the amount of collagen fibers present within the tissue. Including PVAT in the measurement of the aortic wall’s mechanical behavior is important, and it significantly affects the resulting metrics by decreasing aortic stiffness. 

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4. Extracellular Matrix-Based Biomaterials for Cardiovascular Tissue Engineering

   https://doi.org/10.3390/jcdd8110137  

   Khanna, Astha; Zamani, Maedeh; Huang, Ngan F. (November 2021, Journal of Cardiovascular Development and Disease)

   Regenerative medicine and tissue engineering strategies have made remarkable progress in remodeling, replacing, and regenerating damaged cardiovascular tissues. The design of three-dimensional (3D) scaffolds with appropriate biochemical and mechanical characteristics is critical for engineering tissue-engineered replacements. The extracellular matrix (ECM) is a dynamic scaffolding structure characterized by tissue-specific biochemical, biophysical, and mechanical properties that modulates cellular behavior and activates highly regulated signaling pathways. In light of technological advancements, biomaterial-based scaffolds have been developed that better mimic physiological ECM properties, provide signaling cues that modulate cellular behavior, and form functional tissues and organs. In this review, we summarize the in vitro, pre-clinical, and clinical research models that have been employed in the design of ECM-based biomaterials for cardiovascular regenerative medicine. We highlight the research advancements in the incorporation of ECM components into biomaterial-based scaffolds, the engineering of increasingly complex structures using biofabrication and spatial patterning techniques, the regulation of ECMs on vascular differentiation and function, and the translation of ECM-based scaffolds for vascular graft applications. Finally, we discuss the challenges, future perspectives, and directions in the design of next-generation ECM-based biomaterials for cardiovascular tissue engineering and clinical translation. 

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5. Aortic tissue stiffness and tensile strength are correlated with density changes following proteolytic treatment

   https://doi.org/10.1016/j.jbiomech.2024.112226  

   Gueldner, Pete H; Darvish, Cyrus J; Chickanosky, Isabelle KM; Ahlgren, Emma E; Fortunato, Ronald; Chung, Timothy K; Rajagopal, Keshava; Benjamin, Chandler C; Maiti, Spandan; Rajagopal, Kumbakonam R; et al (July 2024, Journal of Biomechanics)

   Introduction: Dissection or rupture of the aorta is accompanied by high mortality rates, and there is a pressing need for better prediction of these events for improved patient management and clinical outcomes. Biomechanically, these events represent a situation wherein the locally acting wall stress exceed the local tissue strength. Based on recent reports for polymers, we hypothesized that aortic tissue failure strength and stiffness are directly associated with tissue mass density. The objective of this work was to test this novel hypothesis for porcine thoracic aorta. Methods: Three tissue specimens from freshly harvested porcine thoracic aorta were treated with either collagenase or elastase to selectively degrade structural proteins in the tissue, or with phosphate buffer saline (control). The tissue mass and volume of each specimen were measured before and after treatment to allow for density calculation, then mechanically tested to failure under uniaxial extension. Results: Protease treatments resulted in statistically significant tissue density reduction (sham vs. collagenase p = 0.02 and sham vs elastase p = 0.003), which in turn was significantly and directly correlated with both ultimate tensile strength (sham vs. collagenase p = 0.02 and sham vs elastase p = 0.03) and tangent modulus (sham vs. collagenase p = 0.007 and sham vs elastase p = 0.03). Conclusions: This work demonstrates for the first time that tissue stiffness and tensile strength are directly correlated with tissue density in proteolytically-treated aorta. These findings constitute an important step towards understanding aortic tissue failure mechanisms and could potentially be leveraged for non-invasive aortic strength assessment through density measurements, which could have implications to clinical care. 

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