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  • 1
    In: Frontiers in Physiology, Frontiers Media SA, Vol. 12 ( 2021-3-29)
    Abstract: Enhanced mineralocorticoid receptor (MR) signaling is critical to the development of endothelial dysfunction and arterial stiffening. However, there is a lack of knowledge about the role of MR-induced adipose tissue inflammation in the genesis of vascular dysfunction in women. In this study, we hypothesize that MR activation in myeloid cells contributes to angiotensin II (Ang II)-induced aortic stiffening and endothelial dysfunction in females via increased pro-inflammatory (M1) macrophage polarization. Female mice lacking MR in myeloid cells (MyMRKO) were infused with Ang II (500 ng/kg/min) for 4 weeks. This was followed by determinations of aortic stiffness and vasomotor responses, as well as measurements of markers of inflammation and macrophage infiltration/polarization in different adipose tissue compartments. MyMRKO mice were protected against Ang II-induced aortic endothelial stiffening, as assessed via atomic force microscopy in aortic explants, and vasorelaxation dysfunction, as measured by aortic wire myography. In alignment, MyMRKO mice were protected against Ang II-induced macrophage infiltration and M1 polarization in visceral adipose tissue (VAT) and thoracic perivascular adipose tissue (tPVAT). Collectively, this study demonstrates a critical role of MR activation in myeloid cells in the pathogenesis of vascular dysfunction in females associated with pro-inflammatory macrophage polarization in VAT and tPVAT. Our data have potential clinical implications for the prevention and management of cardiovascular disease in women, who are disproportionally at higher risk for poor outcomes.
    Type of Medium: Online Resource
    ISSN: 1664-042X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2564217-0
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  • 2
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 76, No. 4 ( 2020-10), p. 1319-1329
    Abstract: Insulin resistance in the vasculature is a characteristic feature of obesity and contributes to the pathogenesis of vascular dysfunction and disease. However, the molecular mechanisms underlying obesity-associated vascular insulin resistance and dysfunction remain poorly understood. We hypothesized that TRAF3IP2 (TRAF3 interacting protein 2), a proinflammatory adaptor molecule known to activate pathological stress pathways and implicated in cardiovascular diseases, plays a causal role in obesity-associated vascular insulin resistance and dysfunction. We tested this hypothesis by employing genetic-manipulation in endothelial cells in vitro, in isolated arteries ex vivo, and diet-induced obesity in a mouse model of TRAF3IP2 ablation in vivo. We show that ectopic expression of TRAF3IP2 blunts insulin signaling in endothelial cells and diminishes endothelium-dependent vasorelaxation in isolated aortic rings. Further, 16 weeks of high fat/high sucrose feeding impaired glucose tolerance, aortic insulin-induced vasorelaxation, and hindlimb postocclusive reactive hyperemia, while increasing blood pressure and arterial stiffness in wild-type male mice. Notably, TRAF3IP2 ablation protected mice from such high fat/high sucrose feeding-induced metabolic and vascular defects. Interestingly, wild-type female mice expressed markedly reduced levels of TRAF3IP2 mRNA independent of diet and were protected against high fat/high sucrose diet-induced vascular dysfunction. These data indicate that TRAF3IP2 plays a causal role in vascular insulin resistance and dysfunction. Specifically, the present findings highlight a sexual dimorphic role of TRAF3IP2 in vascular control and identify it as a promising therapeutic target in vasculometabolic derangements associated with obesity, particularly in males.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2094210-2
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  • 3
    In: Journal of Applied Physiology, American Physiological Society, Vol. 129, No. 2 ( 2020-08-01), p. 283-296
    Abstract: We aimed to examine whether individuals with type 2 diabetes (T2D) exhibit suppressed leg vascular conductance and skeletal muscle capillary perfusion in response to a hyperinsulinemic-euglycemic clamp and to test whether these two variables are positively correlated. Subsequently, we examined whether T2D-associated skeletal muscle microvascular insulin resistance, as well as overall vascular dysfunction, would be ameliorated by an 8-wk walking intervention (45 min at 60% of heart rate reserve, 5 sessions/week). We report that, relative to healthy subjects, overweight and obese individuals with T2D exhibit depressed insulin-stimulated increases in leg vascular conductance, skeletal muscle capillary perfusion, and Akt phosphorylation. Notably, we found that within individuals with T2D, those with lesser increases in leg vascular conductance in response to insulin exhibited the lowest increases in muscle capillary perfusion, suggesting that limited muscle capillary perfusion may be, in part, linked to the impaired ability of the upstream resistance vessels to dilate in response to insulin. Furthermore, we show that the 8-wk walking intervention, which did not evoke weight loss, was insufficient to ameliorate skeletal muscle microvascular insulin resistance in previously sedentary, overweight/obese subjects with T2D, despite high adherence and tolerance. However, the walking intervention did improve ( P 〈 0.05) popliteal artery flow-mediated dilation (+4.52%) and reduced HbA1c (−0.75%). It is possible that physical activity interventions that are longer in duration, engage large muscle groups with recruitment of the maximum number of muscle fibers, and lead to a robust reduction in metabolic risk factors may be required to overhaul microvascular insulin resistance in T2D. NEW & NOTEWORTHY This report provides evidence that in sedentary subjects with type 2 diabetes diminished insulin-stimulated increases in leg vascular conductance and ensuing blunted capillary perfusion in skeletal muscle are not restorable by increased walking alone. More innovative physical activity interventions that ultimately result in a robust mitigation of metabolic risk factors may be vital for reestablishing skeletal muscle microvascular insulin sensitivity in type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    RVK:
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 4
    In: Endocrinology, The Endocrine Society, Vol. 160, No. 12 ( 2019-12-01), p. 2918-2928
    Abstract: Obesity and insulin resistance stiffen the vasculature, with females appearing to be more adversely affected. As augmented arterial stiffness is an independent predictor of cardiovascular disease (CVD), the increased predisposition of women with obesity and insulin resistance to arterial stiffening may explain their heightened risk for CVD. However, the cellular mechanisms by which females are more vulnerable to arterial stiffening associated with obesity and insulin resistance remain largely unknown. In this study, we provide evidence that female mice are more susceptible to Western diet–induced endothelial cell stiffening compared with age-matched males. Mechanistically, we show that the increased stiffening of the vascular intima in Western diet–fed female mice is accompanied by enhanced epithelial sodium channel (ENaC) activity in endothelial cells (EnNaC). Our data further indicate that: (i) estrogen signaling through estrogen receptor α (ERα) increases EnNaC activity to a larger extent in females compared with males, (ii) estrogen-induced activation of EnNaC is mediated by the serum/glucocorticoid inducible kinase 1 (SGK-1), and (iii) estrogen signaling stiffens endothelial cells when nitric oxide is lacking and this stiffening effect can be reduced with amiloride, an ENaC inhibitor. In aggregate, we demonstrate a sexual dimorphism in obesity-associated endothelial stiffening, whereby females are more vulnerable than males. In females, endothelial stiffening with obesity may be attributed to estrogen signaling through the ERα–SGK-1–EnNaC axis, thus establishing a putative therapeutic target for female obesity-related vascular stiffening.
    Type of Medium: Online Resource
    ISSN: 1945-7170
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2019
    detail.hit.zdb_id: 2011695-0
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  • 5
    In: The FASEB Journal, Wiley, Vol. 34, No. S1 ( 2020-04), p. 1-1
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 6
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 321, No. 2 ( 2021-08-01), p. H435-H445
    Abstract: Arterial stiffening, a characteristic feature of obesity and type 2 diabetes, contributes to the development and progression of cardiovascular diseases (CVD). Currently, no effective prophylaxis or therapeutics is available to prevent or treat arterial stiffening. A better understanding of the molecular mechanisms underlying arterial stiffening is vital to identify newer targets and strategies to reduce CVD burden. A major contributor to arterial stiffening is increased collagen deposition. In the 5′-untranslated regions of mRNAs encoding for type I collagen, an evolutionally conserved stem-loop (SL) structure plays an essential role in its stability and post-transcriptional regulation. Here, we show that feeding a high-fat/high-sucrose (HFHS) diet for 28 wk increases adiposity, insulin resistance, and blood pressure in male wild-type littermates. Moreover, arterial stiffness, assessed in vivo via aortic pulse wave velocity, and ex vivo using atomic force microscopy in aortic explants or pressure myography in isolated femoral and mesenteric arteries, was also increased in those mice. Notably, all these indices of arterial stiffness, along with collagen type I levels in the vasculature, were reduced in HFHS-fed mice harboring a mutation in the 5′SL structure, relative to wild-type littermates. This protective vascular phenotype in 5′SL-mutant mice did not associate with a reduction in insulin resistance or blood pressure. These findings implicate the 5′SL structure as a putative therapeutic target to prevent or reverse arterial stiffening and CVD associated with obesity and type 2 diabetes. NEW & NOTEWORTHY In the 5’-untranslated (UTR) regions of mRNAs encoding for type I collagen, an evolutionally conserved SL structure plays an essential role in its stability and posttranscriptional regulation. We demonstrate that a mutation of the SL mRNA structure in the 5’-UTR decreases collagen type I deposition and arterial stiffness in obese mice. Targeting this evolutionarily conserved SL structure may hold promise in the management of arterial stiffening and CVD associated with obesity and type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 7
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 316, No. 2 ( 2019-02-01), p. E156-E167
    Abstract: The role of estrogen receptor-α (ERα) signaling in immunometabolic function is established in females. However, its necessity in males, while appreciated, requires further study. Accordingly, we first determined whether lower metabolic function in male mice compared with females is related to reduced ERα expression. ERα protein expression in metabolically active tissues was lower in males than in females, and this lower expression was associated with worse glucose tolerance. Second, we determined whether ERα is required for optimal immunometabolic function in male mice consuming a chow diet. Despite lower expression of ERα in males, its genetic ablation (KO) caused an insulin-resistant phenotype characterized by enhanced adiposity, glucose intolerance, hepatic steatosis, and metaflammation in adipose tissue and liver. Last, we determined whether ERα is essential for exercise-induced metabolic adaptations. Twelve-week-old wild-type (WT) and ERα KO mice either remained sedentary (SED) or were given access to running wheels (WR) for 10 wk while fed an obesogenic diet. Body weight and fat mass were lower in WR mice regardless of genotype. Daily exercise obliterated immune cell infiltration and inflammatory gene transcripts in adipose tissue in both genotypes. In the liver, however, wheel running suppressed hepatic steatosis and inflammatory gene transcripts in WT but not in KO mice. In conclusion, the present findings indicate that ERα is required for optimal immunometabolic function in male mice despite their reduced ERα protein expression in metabolically active tissues. Furthermore, for the first time, we show that ERα signaling appears to be obligatory for exercise-induced prevention of hepatic steatosis.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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