Aging differentially impacts vasodilation and angiogenesis in arteries from the white and brown adipose tissues

Islam, Torikul; Henson, Grant D.; Machin, Daniel R.; Bramwell, R Colton; Donato, Anthony J.; Lesniewski, Lisa A.

doi:10.1016/j.exger.2020.111126

Cited by 15 publications

(10 citation statements)

References 37 publications

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“…Vasorelaxation was induced with acetylcholine (Ach) following constriction with Phe, and this did reveal a steady decrease in relaxation potential with age that became significantly blunted at 80 weeks ( p = 0.0189; Figure 5b ). This was similar to what had been observed in aged rats (Luttrell et al, 2020 ), and similar to a previous study which demonstrated that B6D2F1 mice (which comprise 50% of the HET3 genome) displayed decreased insulin‐stimulated arterial vasodilation in scWAT, pgWAT, and BAT with age (Islam et al, 2020 ). Perivascular adipose tissue phenotype was assessed across aging, using a previously established reproducible protocol to quantify percentage lipid within mouse PVAT (Tero et al, 2022 ).…”

Section: Resultssupporting

confidence: 91%

“…These observations were similar in HET3 mice (Figure 1g,i ). Data indicate an age‐related decline in adipose tissue total vascularity (Donato et al, 2014 ) and vascular function (Islam et al, 2020 ), which fits with our observations that adipose vessel innervation changes with age in BL6 mice, but this was not observed in HET3 mice despite changes to vascular function with age. Aging adipose tissue is also characterized by chronic inflammation (De Carvalho et al, 2019 ), and in our studies, this was most prominent in visceral pgWAT for both strains and was only prominent in scWAT following rapamycin treatment.…”

Section: Discussionsupporting

confidence: 91%

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Age‐related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment

et al. 2023

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Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased (‘adipose neuropathy’). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose‐resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the incidence of peripheral neuropathy and adipose tissue dysregulation across several ages in both male and female mice. We also investigated the anti‐aging treatment rapamycin, an mTOR inhibitor, as a means to prevent or reduce adipose neuropathy. We found that HET3 mice displayed a reduced neuropathy phenotype compared to inbred C56BL/6 J mice, indicating genetic contributions to this aging phenotype. Compared to female HET3 mice, male HET3 mice had worse neuropathic phenotypes by 62 weeks of age. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126 weeks), after reproductive senescence. We found that rapamycin overall had little impact on neuropathy measures, and actually worsened adipose tissue inflammation and fibrosis. Despite its success as a longevity treatment in mice, higher doses and longer delivery paradigms for rapamycin may lead to a disconnect between life span and beneficial health outcomes.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Age‐related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment

et al. 2023

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“…Advancing age is accompanied by metabolic dysfunction such as an impairment in glucose and lipid metabolism (Chia et al, 2018 ; Petersen et al, 2017 ; Rines et al, 2016 ). The mechanisms that underlie metabolic dysfunction in old age are multifaceted (Islam et al, 2020 ). However, emerging evidence suggests that metabolic dysfunction in old age is concomitant with the accumulation of senescent cells across many organs and tissues including adipose tissue and liver (Borghesan et al, 2020 ; Xu, Palmer, et al, 2015 ; Yousefzadeh et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

et al. 2023

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Aging results in an elevated burden of senescent cells, senescence‐associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low‐grade inflammation and a host of age‐related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age‐related increase in senescence‐associated β‐galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age‐related increase in the expression of a subset of pro‐inflammatory SASP genes ( mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10 ), crown‐like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age‐related difference in glucose tolerance, D&Q treatment improved fasting blood glucose ( p = 0.001) and glucose tolerance ( p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin‐stimulated suppression of plasma NEFAs ( p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance ( p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.

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“…Endothelial-independent dilation was assessed by measuring vasodilation in response to the cumulative addition of the exogenous NO donor sodium nitroprusside (SNP [sodium nitroprusside]; 10 −10 to 10 −4 mol/L). 30 Vessel diameters were measured using the MyoView software (DMT, Inc, Atlanta, GA). All dose-response data are presented as the percentage of possible dilation after preconstriction to phenylephrine.…”

Section: Methodsmentioning

confidence: 99%

Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice

Islam,

Cai,

Allen

et al. 2024

ATVB

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BACKGROUND: Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. METHODS: We used mouse models of constitutive endothelial cell–specific Arf6 deletion (Arf6 f/ − Tie2Cre) and tamoxifen-inducible Arf6 knockout (Arf6 f/f Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere–based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy. RESULTS: Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated NO bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside–mediated vasodilation. Endothelial cell–specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow–fed mice and glucose intolerance in high-fat diet–fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. CONCLUSIONS: Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

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Aging differentially impacts vasodilation and angiogenesis in arteries from the white and brown adipose tissues

Cited by 15 publications

References 37 publications

Age‐related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment

Age‐related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice

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