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Effects of perivascular adipose tissue (PVAT) on large elastic artery stiffness. (A) Thoracic PVAT was removed from donor mice and transplanted into young recipient for 8 weeks. (B) Aortic pulse wave velocity (aPWV) and (C) ex vivo arterial stiffness in young recipient mice receiving PVAT from young, old, and old TEMPOL-treated donors after 8 weeks. (D) Arterial stiffness in aortic segments cultured for 72 h with (+) or without (−) perivascular adipose tissue from additional young and old control mice in the presence (+) or absence (−) of TEMPOL (N = 4–6/group); Values are means ± S.E. *P < 0.05 vs. all; # P < 0.05 vs. Young PVAT and Old TEMPOL PVAT; $P < 0.05 vs. Young; Old PVAT (−), TEMPOL (−) and Old PVAT (+), TEMPOL (+).
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We tested the hypothesis that superoxide signaling within aortic perivascular adipose tissue (PVAT) contributes to large elastic artery stiffening in old mice. Young (4-6 mo), old (26-28 mo), and old treated with TEMPOL, a superoxide scavenger (1mM in drinking water for 3 weeks), male C57BL6/N mice were studied. Compared with young, old had greater...
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... production was increased in whole tissue samples of PVAT surrounding the thoracic aorta (Fig. 1C), and in adipocytes isolated from PVAT of old control compared with young control mice (Fig. S2) (both, P < 0.05). TEMPOL normalized aortic PVAT superoxide production in whole tissue samples from old mice to young control levels (Fig. 1C) (P < ...
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... aorta PVAT was removed from young control, old control, and old TEMPOL-treated donors and transplanted directly onto the abdominal aorta of young recipient mice for 8 weeks (Fig 2A). Young recipient mice transplanted with PVAT from old animals had greater aortic stiffness as indicated by increased aPWV and ex vivo intrinsic mechanical stiffness compared with those transplanted with PVAT from young donors (Fig. 2B,C) (both, P < 0.05). ...
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... old TEMPOL-treated donors and transplanted directly onto the abdominal aorta of young recipient mice for 8 weeks (Fig 2A). Young recipient mice transplanted with PVAT from old animals had greater aortic stiffness as indicated by increased aPWV and ex vivo intrinsic mechanical stiffness compared with those transplanted with PVAT from young donors (Fig. 2B,C) (both, P < 0.05). TEMPOL treatment in old donors abolished the increases in aPWV and ex vivo intrinsic mechanical stiffness observed with transplantation into young recipient mice ( Aging Cell (2014) 13, pp576-578 Doi: ...
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... further determine the effects of PVAT on arterial stiffness, aortic segments from additional young and old control mice were cultured in the presence (+) or absence (-) of PVAT for 72 h. Intrinsic mechanical stiffness was greater in aortic segments from old (+) PVAT compared with all aortic segments from young control mice (Fig. 2D) (all, P < 0.05). Compared with aortic segments from old (À) PVAT, samples from old (+) PVAT had greater intrinsic stiffness (Fig. 2D) (P < 0.05). TEMPOL reversed the intrinsic mechanical properties in arterial segments (+) PVAT to levels similar to old (À) PVAT (Fig. 2D) (P < ...
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... mice were cultured in the presence (+) or absence (-) of PVAT for 72 h. Intrinsic mechanical stiffness was greater in aortic segments from old (+) PVAT compared with all aortic segments from young control mice (Fig. 2D) (all, P < 0.05). Compared with aortic segments from old (À) PVAT, samples from old (+) PVAT had greater intrinsic stiffness (Fig. 2D) (P < 0.05). TEMPOL reversed the intrinsic mechanical properties in arterial segments (+) PVAT to levels similar to old (À) PVAT (Fig. 2D) (P < ...
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... from old (+) PVAT compared with all aortic segments from young control mice (Fig. 2D) (all, P < 0.05). Compared with aortic segments from old (À) PVAT, samples from old (+) PVAT had greater intrinsic stiffness (Fig. 2D) (P < 0.05). TEMPOL reversed the intrinsic mechanical properties in arterial segments (+) PVAT to levels similar to old (À) PVAT (Fig. 2D) (P < ...
Citations
... Bioinformatic analysis by LRT reported 9.5% upregulated and 9% downregulated genes for MR flox mice whereas 4.6% upregulated and 2.9% downregulated genes for MR LysMcre mice over the baseline with adjusted p value < 0.1 out of 20,122 filtered nonzero reads counts ( Supplementary Fig. S2). Pathway enrichment analysis (Fig. 1A, B) showed that several biological processes related to inflammation and cell metabolism and involved in cardiovascular aging [21,32,38,52,61] were regulated. Of note, over course of aging signaling pathways related to regulation of inflammation as cytokine-mediated signaling pathway, cytokine production, immune response, T cell activation were upregulated while pathways related to cell metabolism as lipid catabolic process, peptide metabolic process, ATP biosynthetic process, organic acid metabolic process were downregulated in macrophages from hearts of MR flox mice. ...
Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid receptor (MR) activation in macrophages critically regulates inflammatory and fibrotic processes. However, macrophage-specific mechanisms and the role of the macrophage MR for the regulation of inflammation and fibrotic remodeling in the aging heart have not yet been elucidated. Transcriptome profiling of cardiac macrophages from male/female young (4 months-old), middle (12 months-old) and old (18 and 24 months-old) mice revealed that myeloid cell-restricted MR deficiency prevents macrophage differentiation toward a pro-inflammatory phenotype. Pathway enrichment analysis showed that several biological processes related to inflammation and cell metabolism were modulated by the MR in aged macrophages. Further, transcriptome analysis of aged cardiac fibroblasts revealed that macrophage MR deficiency reduced the activation of pathways related to inflammation and upregulation of ZBTB16, a transcription factor involved in fibrosis. Phenotypic characterization of macrophages showed a progressive replacement of the TIMD4⁺MHC-IIneg/low macrophage population by TIMD4⁺MHC-IIint/high and TIMD4–MHC-IIint/high macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4⁺/TIMD4–macrophages and fibroblasts from old MRflox/MRLysMCre hearts, we showed that the inflammatory crosstalk between TIMD4– macrophages and fibroblasts may imply the macrophage MR and the release of mitochondrial superoxide anions. Macrophage MR deficiency reduced the expansion of the TIMD4– macrophage population and the emergence of fibrotic niches in the aging heart, thereby protecting against cardiac inflammation, fibrosis, and dysfunction. This study highlights the MR as an important mediator of cardiac macrophage inflammaging and age-related fibrotic remodeling.
... Of note, PVAT-intact aortic preparations stimulated by noradrenaline show an increased level of superoxide anion that was hypothesized to modulate vessel contraction directly or after dismutation to hydrogen peroxide [95]. Higher levels of superoxide anion are measured in PVAT of old male C57BL6/N mice as compared to young counterparts; this ROS was associated with enhanced arterial stiffness, though the contractile function was not directly assessed in this study [182]. ...
Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to cardiovascular disease onset and progression. In the context of vascular tone regulation, under physiological conditions, PVAT exerts a potent anticontractile effect by releasing a plethora of vasoactive substances, including NO, H 2 S, H 2 O 2 , prostacyclin, palmitic acid methyl ester, angiotensin 1-7, adiponectin, leptin, and omentin. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and increasing that of pro-contractile factors, including superoxide anion, angiotensin II, catecholamines, prostaglandins, chemerin, resistin, and visfatin. The present review discusses the regulatory effect of PVAT on vascular tone and the factors involved. In this scenario, dissecting the precise role of PVAT is a prerequisite to the development of PVAT-targeted therapies.
... Transplantation of aged PVAT also increased thickness of aortic wall and lumen diameter, and caused the accumulation of collagens in arterial adventitial layer of young recipient mice. In addition, prior treatment of the superoxide scavenger TEMPOL alleviated the stiffness-promoting effect of aged PVAT in young recipient mice [58]. ...
... Compared to young mice, increased amount of pro-inflammatory cytokines secreted by PVAT was reported in aged mice based on cytokine array data. Notably, higher levels of IL-6, granulocyte macrophage colony stimulating factor, MCP-1, C-X-C motif chemokine ligand (CXCL) 1 and CXCL2 in aged mice were observed [58]. ...
Perivascular adipose tissue (PVAT) refers to the aggregate of adipose tissue surrounding the vasculature, exhibiting the phenotypes of white, beige and brown adipocytes. PVAT has emerged as an active modulator of vascular homeostasis and pathogenesis of cardiovascular diseases in addition to its structural role to provide mechanical support to blood vessels. More specifically, PVAT is closely involved in the regulation of reactive oxygen species (ROS) homeostasis and inflammation along the vascular tree, through the tight interaction between PVAT and cellular components of the vascular wall. Furthermore, the phenotype-genotype of PVAT at different regions of vasculature varies corresponding to different cardiovascular risks. During ageing and obesity, the cellular proportions and signaling pathways of PVAT vary in favor of cardiovascular pathogenesis by promoting ROS generation and inflammation. Physiological means and drugs that alter PVAT mass, components and signaling may provide new therapeutic insights in the treatment of cardiovascular diseases. In this review, we aim to provide an updated understanding towards PVAT in the context of redox regulation, and to highlight the therapeutic potential of targeting PVAT against cardiovascular complications.
... Increased O 2 − _ signaling (Fleenor et al., 2014) and ...
Increasing scientific interest has been directed to sex as a biological and decisive factor on several diseases. Several different mechanisms orchestrate vascular function, as well as vascular dysfunction in cardiovascular and metabolic diseases in males and females. Certain vascular sex differences are present throughout life, while others are more evident before the menopause, suggesting two important and correlated drivers: genetic and hormonal factors. With the increasing life expectancy and aging population, studies on aging-related diseases and aging-related physiological changes have steeply grown and, with them, the use of aging animal models. Mouse and rat models of aging, the most studied laboratory animals in aging research, exhibit sex differences in many systems and physiological functions, as well as sex differences in the aging process and aging-associated cardiovascular changes. In the present review, we introduce the most common aging and senescence-accelerated animal models and emphasize that sex is a biological variable that should be considered in aging studies. Sex differences in the cardiovascular system, with a focus on sex differences in aging-associated vascular alterations (endothelial dysfunction, remodeling and oxidative and inflammatory processes) in these animal models are reviewed and discussed.
... Although incubations were only 72 hours, we observed a similar magnitude increase in intrinsic mechanical stiffness (≈30%) as following dietary supplementation, and our laboratory has previously shown that this duration of incubation is sufficient to alter stiffness in response to diverse stimuli. 30,51 It is possible that aortic stiffness can be altered more quickly ex vivo due to the absence of counter-regulatory functional (nonstructural) factors that can influence PWV in vivo, including BP, vascular tone, and sympathetic nervous system activity. Such influences may initially compensate for TMAO-induced changes in the extracellular matrix, thus delaying detectable differences in aortic PWV. ...
Aging is associated with stiffening of the large elastic arteries and consequent increases in systolic blood pressure (SBP), which together increase cardiovascular disease risk; however, the upstream mechanisms are incompletely understood. Using complementary translational approaches in mice and humans, we investigated the role of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) in age-related aortic stiffening and increased SBP. Aortic stiffness was measured using carotid-femoral or aortic pulse wave velocity (PWV) in humans and mice, respectively. Study 1: Plasma TMAO concentrations were elevated (P<0.001) in healthy middle-aged to older (6.3±5.8 µmol/L) versus young (1.8±1.4 µmol/L) humans and positively related to carotid-femoral PWV (r
2
=0.15, P<0.0001) and SBP (r
2
=0.09, P<0.001), independent of traditional cardiovascular risk factors. Study 2: Dietary supplementation with TMAO increased aPWV in young mice and exacerbated the already elevated aPWV of old mice, accompanied by increases in SBP of ≈10 mm Hg in both groups. TMAO-supplemented versus control-fed mice also had higher intrinsic mechanical stiffness of the aorta (stress-strain testing) associated with higher aortic abundance of advanced glycation end-products, which form crosslinks between structural proteins to promote aortic stiffening. Study 3: Ex vivo incubation of aortic rings with TMAO increased intrinsic stiffness, which was attenuated by the advanced glycation end-products crosslink breaker alagebrium and prevented by inhibition of superoxide signaling. TMAO induces aortic stiffening and increases SBP via formation of advanced glycation end-products and superoxide-stimulated oxidative stress, which together increase intrinsic wall stiffness. Increases in circulating TMAO with aging represent a novel therapeutic target for reducing risk of aortic stiffening-related clinical disorders.
... Intrinsic mechanical stiffness. Two ß1-mm segments of the thoracic aorta were used for determination of intrinsic mechanical stiffness by incremental stress-strain testing via wire myography, as described previously by our laboratory (Fleenor et al. 2014;LaRocca et al. 2014;Gioscia-Ryan et al. 2018). Aortic segments were loaded into a warmed (37C°) wire myograph chamber (DMT) containing calcium-free phosphate-buffered saline. ...
Key points
The results of the present study establish the temporal pattern of age‐related vascular dysfunction across the adult lifespan in sedentary mice consuming a non‐Western diet, and the underlying mechanisms
The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice
They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption
Overall, the results indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise‐associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern
Abstract
Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium‐dependent dilatation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular ageing occurs in the presence of differences in diet and physical activity, but the interactive effects of these factors are unknown. We assessed carotid artery EDD and aPWV across the lifespan in mice consuming standard (normal) low‐fat chow (NC) or a high‐fat/high‐sucrose Western diet (WD) in the absence (sedentary, SED) or presence (voluntary wheel running, VWR) of aerobic exercise. Ageing impaired nitric oxide‐mediated EDD (peak EDD 88 ± 12% 6 months P = 0.003 vs. 59 ± 9% 27 months NC‐SED), which was accelerated by WD (60 ± 18% 6 months WD‐SED). In NC mice, aPWV increased 32% with age (423 ± 13 cm/s at 24 months P < 0.001 vs. 321 ± 12 cm/s at 6 months) and absolute values were an additional ∼10% higher at any age in WD mice (P = 0.042 vs. NC‐SED). Increases in aPWV with age in NC and WD mice were associated with 30–65% increases in aortic intrinsic wall stiffness (6 vs. 19–27 months, P = 0.007). Lifelong aerobic exercise prevented age‐ and WD‐related vascular dysfunction across the lifespan, and this protection appeared to be mediated by mitigation of vascular mitochondrial oxidative stress and inflammation. Our results depict the temporal impairment of vascular function over the lifespan in mice, acceleration and exacerbation of that dysfunction with WD consumption, the remarkable protective effects of voluntary aerobic exercise, and the underlying mechanisms.
... In obese mice, treatment with SRT1720 (a SIRT1 specific activator) prolongs the lifespan and reverses obesity-induced organ damages via normalizing the acetylation of PGC-1α to promote mitochondrial biogenesis in adipose tissue [202]. Activation of SIRT1 can normalize inflammatory insult-induced [203] or oxidative stress-induced adipokines dysregulation from adipose tissue and prevent arterial remodeling [204,205]. Moreover, resveratrol, a polyphenol that can activate SIRT1, can ameliorate adipokine release from dysregulated PVAT via the SIRT1/AMPK pathway [206]. ...
Obesity is a major risk factor for most metabolic and cardiovascular disorders. Adipose tissue is an important endocrine organ that modulates metabolic and cardiovascular health by secreting signaling molecules. Oxidative stress is a common mechanism associated with metabolic and cardiovascular complications including obesity, type 2 diabetes, and hypertension. Oxidative stress can cause adipose tissue dysfunction. Accumulating data from both humans and experimental animal models suggest that adipose tissue function and oxidative stress have an innate connection with the intrinsic biological clock. Circadian clock orchestrates biological processes in adjusting to daily environmental changes according to internal or external cues. Recent studies have identified the genes and molecular pathways exhibiting circadian expression patterns in adipose tissue. Disruption of the circadian rhythmicity has been suggested to augment oxidative stress and aberrate adipose tissue function and metabolism. Therefore, circadian machinery in the adipose tissue may be a novel therapeutic target for the prevention and treatment of metabolic and cardiovascular diseases. In this review, we summarize recent findings on circadian rhythm and oxidative stress in adipose tissue, dissect the key components that play a role in regulating the clock rhythm, oxidative stress and adipose tissue function, and discuss the potential use of antioxidant treatment on metabolic and cardiovascular diseases by targeting the adipose clock.
... In obese mice, treatment with the SIRT1 specific activator SRT1720 could prolong the lifespan and reverse HFD-induced organ damage via normalizing the acetylation of PGC-1α in adipose tissue [136]. Moreover, activation of SIRT1 abolishes dysregulated PVAT adipokine release after inflammatory insult [137] and reduces inflammatory cytokines release which promotes arterial remodeling in aged mice [138]. On the other hand, resveratrol can ameliorate adipokine release from dysregulated PVAT by the SIRT1/AMPK pathway [139]. ...
... The activation of the SIRT1/AMPK signaling in PVAT can regulate adipokine expression, ameliorate endothelial dysfunction caused by inhibiting NFκB activation, and alter PVAT inflammation induced by fructose- [141] or HFD-feeding [137]. The oxidative stress in PVAT may lead to increased pro-inflammatory cytokine and chemokine secretion, and the superoxide derived from PVAT promotes artery stiffening in aged mice [138]. Resveratrol can also alleviate oxidative stress-induced cytokine release from PVAT, and subsequently improve arterial wall hypertrophy and adventitial collagen I accumulation to prevent arterial stiffening in aged mice [140]. ...
Perivascular adipose tissue (PVAT) is the connective tissue surrounding most of the systemic blood vessels. PVAT is now recognized as an important endocrine tissue that maintains vascular homeostasis. Healthy PVAT has anticontractile, anti-inflammatory, and antioxidative roles. Vascular oxidative stress is an important pathophysiological event in cardiometabolic complications of obesity, type 2 diabetes, and hypertension. Accumulating data from both humans and experimental animal models suggests that PVAT dysfunction is potentially linked to cardiovascular diseases, and associated with augmented vascular inflammation, oxidative stress, and arterial remodeling. Reactive oxygen species produced from PVAT can be originated from mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and uncoupled endothelial nitric oxide synthase. PVAT can also sense vascular paracrine signals and response by secreting vasoactive adipokines. Therefore, PVAT may constitute a novel therapeutic target for the prevention and treatment of cardiovascular diseases. In this review, we summarize recent findings on PVAT functions, ROS production, and oxidative stress in different pathophysiological settings and discuss the potential antioxidant therapies for cardiovascular diseases by targeting PVAT.
... Noncardiac phenotypes likely contribute to the age-related exercise intolerance seen in this model and need to be further investigated. Third, while no differences in systemic arterial pressure were detected between young and old mice, we did not assess for changes in aortic stiffness, which increases with age and could also be contributing to the pathologic cardiac hypertrophy phenotype seen in this aged mouse model (Fleenor et al., 2014). Lastly, altered pathways were identified using RNAseq on whole heart extracts. ...
Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24–30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age‐related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF.
... The activation of Sirt1 can abolish dysregulated PVAT adipokine release after inflammatory insult [87] and also reduce inflammatory cytokines release to improve arterial wall hypertrophy and adventitial collagen I accumulation, which resulted in arterial stiffness in aged mice [88]. Sirt1 in PVAT is also proven to regulate adiponectin secretion through the interaction with FoxO1 protein [89]. ...
Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.
