Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes

Moudt, Sofie De; Hendrickx, Jhana O.; Neutel, Cédric; Munck, Dorien De; Leloup, Arthur; Meyer, Guido R.Y. De; Martinet, Wim; Fransen, Paul

doi:10.1038/s42003-022-03563-x

Cited by 16 publications

(13 citation statements)

References 68 publications

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“…Phenotypic switching has been described in a multitude of hypertensive animal models (Choi et al, 2019;Galmiche et al, 2013;Huang et al, 2021;Zhou, Lee, Stoll, Ma, Wiener, et al, 2017), which are usually also characterized by elevated contractile responses. Previous work by our research group also described that the loss of nuclear myocardin coincides with increased α 1 -mediated contraction in spontaneously aging C57Bl/6 mice (De Moudt et al, 2022b). Therefore, this finding is not completely at odds with scientific consensus knowledge.…”

Section: Vsmc Phenotypic Switch Migration and Proliferationsupporting

confidence: 58%

“…We previously reported that aortic VSMC contraction significantly alters the biomechanical properties of mouse aortic tissue (Leloup et al, 2019 ), which was recently confirmed for tissue specimens from the human descending thoracic aorta (Franchini et al, 2022 ). Aortic biomechanical properties and the role of VSMC contraction in aortic stiffness regulation were also shown to be altered during aging (Amabili et al, 2020 , 2021 ; De Moudt et al, 2022b ). Following these mechanical characterizations of healthy aortic tissue upon VSMC activation, we therefore now aim to provide improved insight in the biomechanical design of aortic tissue during cardiovascular disease development.…”

Section: Introductionmentioning

confidence: 99%

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Disparate biomechanical properties of the aorta in non‐aneurysmal and aneurysmal mice treated with angiotensin II

Moudt

Hendrickx

Meyer

et al. 2022

Physiological Reports

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In vivo angiotensin II (AngII)-treatment is a widely used experimental model to induce cardiovascular disease and results in a high likelihood of abdominal aorta aneurysm (AAA) formation. This involves progressive and irreversible focal dilation of the abdominal aorta and induces adverse aortic connective tissue remodeling contributing to aortic wall stiffening through inflammation, elastin degradation, and collagen restructuring. Hence, the present study aimed to investigate how AAA formation in AngII-treated mice affects aortic function and biomechanics. To this end, C57Bl/6J mice were treated with AngII (1000 ng/[kg.min]) or PBS infusion for 28 days. Peripheral blood pressure, echocardiography, and aortic pulse wave velocity were measured in vivo. Thoracic aorta rings were studied ex vivo in organ chambers, while aortic vascular smooth muscle cell (VSMC) phenotype was investigated histologically. We confirmed peripheral hypertension, cardiac hypertrophy, aortic stiffening, and increased VSMC proliferation and migration after AngII-treatment. Abdominal aorta aneurysm formation was observed in 8/13 AngII-treated mice. Ex vivo thoracic aortic rings of both aneurysmal and non-aneurysmal AngII-treated mice showed high isobaric aortic stiffness, endothelial dysfunction, heightened α 1 -adrenergic contractility, and altered VSMC contractile calcium signaling. However, aortic biomechanics were differently affected, with heightened α 1 -adrenoreceptor mediated aortic stiffening in non-aneurysmal mice, whereas contraction-dependent stiffening was impaired in aneurysmal mice. In conclusion, although aneurysmal and non-aneurysmal 4-week AngII-treated mice displayed similar changes in aortic physiology, aortic biomechanics were dissimilarly affected.

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Section: Vsmc Phenotypic Switch Migration and Proliferationsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Disparate biomechanical properties of the aorta in non‐aneurysmal and aneurysmal mice treated with angiotensin II

Moudt

Hendrickx

Meyer

et al. 2022

Physiological Reports

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“…male C57BL/6 mice exhibited increased aortic contraction compared to younger 5 mo. mice in response to PE (30). Similarly, in this study thoracic aortic contraction was increased in both 12 mo.…”

Section: Resultsmentioning

confidence: 99%

OxLDL/LOX-1 Mediated Sex, Age, and Cell Dependent Alterations in Mouse Thoracic Aortic Vascular Reactivity

Wendt,

Gonzales

2023

Preprint

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Elevated oxidized low-density lipoprotein (oxLDL) is a risk factor and component that worsens cardiovascular disease states. OxLDL can elicit its detrimental action, via lectin-like oxLDL receptor 1 (LOX-1) and has been shown to disrupt vascular function. In this study, we determined whether oxLDL, via LOX-1, alters aortic vascular reactivity and determined if sex differences exist. Thoracic aortic endothelium-intact or -denuded ring segments were isolated from intact C57BL/6J female and male mice and incubated with oxLDL ex vivo (50ug/dL; 2h). Using wire myography, cumulative concentration-response curves to phenylephrine (PE) were generated to determine contractile responses. From these curves, the EC50 was determined and used to contract rings to assess acetylcholine (ACh) dependent relaxation. Calculated aortic stiffness and remodeling, as well as mRNA expression of vasoactive and pro-inflammatory mediators were assessed. BI-0115 (10μM; selective LOX-1 inhibitor) was used to determine LOX-1 dependence. We observed differential sex, age, endothelial cell, and LOX-1 dependent alterations to the efficacy of PE-induced contractile responses and ACh-mediated vasorelaxation in the thoracic aortic rings following oxLDL exposure. Additionally, we observed a distinct sex and age effect on thoracic aortic stiffness following exposure to oxLDL. There was also a sex effect on calculated vessel diameter, as well as an age effect on oxLDL-mediated inward remodeling that was LOX-1 dependent. Thus, LOX-1 inhibition and the resulting attenuation of oxLDL/endothelial-mediated alterations in aortic function suggests that there are differential sex differences in the role of oxLDL/LOX-1 in the thoracic aorta of male and female mice.NEW & NOTEWORTHYWe investigated the effects of oxidized low-density lipoprotein (oxLDL) via the LOX-1 receptor on murine thoracic aortic vasoreactivity, stiffness, and remodeling across age and sex. Acute exposure to oxLDL led to altered vasoreactivity, endothelial dysfunction, and changes in aortic stiffness and remodeling. These effects were in-part age, sex, endothelial, and LOX-1 dependent. This study reveals potential complex interactions in oxLDL/LOX-1-mediated vascular responses that could serve as potential therapeutic intervention for vascular diseases such as atherosclerosis.

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“…Therefore, it is unsurprising that the effects on endothelial dysfunction and vascular remodeling are not parallel. The aged mice used in this study are already in the completion stage of aortic wall thickening (De Moudt et al, 2022), and BRJ supplementation may have the effect of suppressing the development of thickening but not the effect of regressing it. Alternatively, it may have been necessary to continue the supplementation for a longer period for the regression effect to appear.…”

Section: Discussionmentioning

confidence: 99%

Effects of beetroot juice supplementation on vascular functional and structural changes in aged mice

Tawa

Nakagawa

Ohkita

2023

Physiological Reports

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This study investigated whether beetroot juice (BRJ) ingestion ameliorates aging-induced functional and structural changes in vasculature. Aged mice (98-100 weeks old) were supplemented with BRJ (nitrate: 3.5 mmol/L) or drinking water for 4 weeks and compared with young mice (12-15 weeks old). The vasorelaxant response of isolated aortas to acetylcholine was markedly weaker in aged mice than in young mice, but the attenuated relaxation was significantly improved in BRJ-supplemented aged mice. The acetylcholine-induced relaxation was completely abolished by N ω -nitro-l-arginine methyl ester in all groups.Additionally, the response to sodium nitroprusside was comparable among the three groups. The aortic medial thickness was significantly greater in aged mice than in young mice, and BRJ supplementation did not suppress this thickening. Plasma nitrate levels were significantly higher in BRJ-supplemented aged mice than in non-supplemented aged mice. Conversely, non-supplemented aged mice had high plasma levels of thiobarbituric acid-reactive substances, but the levels were suppressed in BRJ-supplemented aged mice. These findings suggest that BRJ ingestion improves vascular endothelial dysfunction associated with aging, at least in part, by enhancing nitric oxide bioavailability and reducing oxidative stress. Therefore, beetroot ingestion may be a highly useful self-medication option to prevent vascular aging.

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Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes

Cited by 16 publications

References 68 publications

Disparate biomechanical properties of the aorta in non‐aneurysmal and aneurysmal mice treated with angiotensin II

Disparate biomechanical properties of the aorta in non‐aneurysmal and aneurysmal mice treated with angiotensin II

OxLDL/LOX-1 Mediated Sex, Age, and Cell Dependent Alterations in Mouse Thoracic Aortic Vascular Reactivity

Effects of beetroot juice supplementation on vascular functional and structural changes in aged mice

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