Aerobic Exercise Training Prevents the Onset of Endothelial Dysfunction via Increased Nitric Oxide Bioavailability and Reduced Reactive Oxygen Species in an Experimental Model of Menopause

Braga, Viviane A. V. N.; Couto, Gisele Kruger; Lazzarin, Mariana Cruz; Rossoni, Luciana Venturini; Medeiros, Alessandra

doi:10.1371/journal.pone.0125388

Cited by 21 publications

(29 citation statements)

References 47 publications

(66 reference statements)

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“…It is well known that regular aerobic exercise improves the quality of life of patients with CF through increasing expectoration of the sputum and ameliorating the decline in lung function (29,35). Exercise also enhances NO bioavailability (3,4,9). In the present study a positive correlation between the PORH-to-LTH ratio and exercise capacity suggests that a greater exercise capacity positively impacts microvascular function in CF.…”

Section: Microvascular Function and Disease Severity: Clinical Relevancesupporting

confidence: 56%

Evidence of microvascular dysfunction in patients with cystic fibrosis

Rodriguez‐Miguelez

Thomas

Seigler

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Rodriguez-Miguelez P, Thomas J, Seigler N, Crandall R, McKie KT, Forseen C, Harris RA. Evidence of microvascular dysfunction in patients with cystic fibrosis. Am J Physiol Heart Circ Physiol 310: H1479 -H1485, 2016. First published April 15, 2016 doi:10.1152/ajpheart.00136.2016.-Cystic fibrosis (CF) is a genetic, multisystemic disorder with broad clinical manifestations apart from the well-characterized pulmonary dysfunction. Recent findings have described impairment in conduit vessel function in patients with CF; however, whether microvascular function is affected in this population has yet to be elucidated. Using laser-Doppler imaging, we evaluated microvascular function through postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh). PORH [518 Ϯ 174% (CF) and 801 Ϯ 125% (control), P ϭ 0.039], LTH [1,338 Ϯ 436% (CF) and 1,574 Ϯ 620% (control), P ϭ 0.045], and iontophoresis with ACh [416 Ϯ 140% (CF) and 617 Ϯ 143% (control), P ϭ 0.032] were significantly lower in patients with CF than control subjects. In addition, the ratio of PORH to LTH was significantly (P ϭ 0.043) lower in patients with CF (55.3 Ϯ 5.1%) than control subjects (68.8 Ϯ 3.1%). Significant positive correlations between LTH and forced expiratory volume in 1 s (%predicted) (r ϭ 0.441, P ϭ 0.013) and between the PORH-to-LTH ratio and exercise capacity (r ϭ 0.350, P ϭ 0.049) were observed. These data provide evidence of microvascular dysfunction in patients with CF compared with control subjects. In addition, our data demonstrate a complex relationship between microvascular function and classical markers of disease severity (i.e., pulmonary function and exercise capacity) in CF. CYSTIC FIBROSIS (CF) is an inherited disorder that is predominantly characterized by pulmonary dysfunction; however, broader clinical manifestations, such as gastrointestinal, immune, endocrine, and musculoskeletal dysfunctions, are also present (36). Recently, our group reported conduit vascular endothelial dysfunction in young patients with CF (39). Importantly, this vascular impairment was observed in a population that exhibited preserved spirometric function and exercise capacity, which suggests a systemic consequence prior to the decrease in pulmonary function. Despite these recent observations, there appears to be a lack of understanding of the general functionality of the endothelium in CF.Impairments in endothelial function are highly related to a reduction in the bioavailability of nitric oxide (NO), a key vasodilator involved in the regulation of vessel tone and endothelium integrity (24). Decreases in NO balance have also been shown to contribute to impaired endothelial microvascular vasodilation (44). With use of laser-Doppler imaging technology, cutaneous blood flux can be quantified (45) to represent an accessible model of microvascular function (17). Postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh), in combination with laser technology...

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Section: Microvascular Function and Disease Severity: Clinical Relevancesupporting

confidence: 56%

Evidence of microvascular dysfunction in patients with cystic fibrosis

Rodriguez‐Miguelez

Thomas

Seigler

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Thus, one possibility is that exercise training leads to signaling through the ERRα pathway in recent post‐menopausal women, whereas this function may be lost if training is initiated several years after menopause. This timing hypothesis does also fit with animal experiments showing beneficial effects of exercise training on vascular function in ovariectomized rats studied within 1 week of surgery . As proposed in Figure , the high estrogen levels in pre‐menopausal women may suppress the ERRα pathway.…”

Section: Introductionsupporting

confidence: 73%

“…Not all studies have, however, shown that estrogen supplementation is required for beneficial effects of exercise training on vascular function. Several studies on rodents, in which vascular function has been assessed in isolated arteries, have demonstrated that exercise training is effective in female ovariectomized rodents . Moreover, 2 recent studies on late pre‐menopausal and early post‐menopausal women, who were on average 3 years within the menopausal transition, have shown that exercise training induces similar, and, for some variables, even better effects on vascular function and markers of vascular function in post‐menopausal compared to pre‐menopausal women .…”

Section: Introductionmentioning

confidence: 99%

Limb vascular function in women-Effects of female sex hormones and physical activity

Hellsten

Gliemann

2018

Transl Sports Med

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Throughout life, women are subjected to both acute fluctuations in sex hormones, associated with the menstrual cycle, and chronic changes following the onset of menopause. Female sex hormones, and in particular estrogen, strongly influence cardiovascular function such as the regulation of vascular tone and oxidative stress and thereby functions such as oxygen delivery and blood pressure. The acute hormonal fluctuations do not substantially impact health, but their influence should be considered with regard to measurements of vascular function. The chronic hormonal change with menopause strongly impacts the vasculature and markedly increases the risk of cardiovascular events. Physical activity activates signaling pathways also triggered by estrogen; therefore, exercise training could be an effective means of reducing the deleterious effects of estrogen loss at menopause. However, findings are divergent with some reporting marked improvements in vascular health with physical activity and others showing lower gains compared to age-matched males. Potential explanations for this discrepancy in findings are timing after menopause and training mode, aspects that should be further addressed in future studies. Physical activity should be recommended for women of all ages, but the most essential timing for maintenance of vascular health may be from menopause and onwards. K E Y W O R D Sblood vessel, estrogen, exercise, nitric oxide, prostacyclin | INTRODUCTIONFemale sex hormones, and in particular estrogen, are known to have numerous protective and functional roles in the vasculature including regulation of vasodilator systems, vascular growth, reduction in platelet reactivity, and vascular inflammation. 1,2 Alterations in the levels of sex hormones occur short term during the menstrual cycle and chronically at menopause with an almost complete loss of progesterone and estrogen. The chronic alterations in sex hormones at menopause greatly influence a number of aspects in women's health and substantially impact on the cardiovascular system resulting in impairment in vascular function 3,4 and a markedly increased prevalence of cardiovascular disease. 5 In this overview, we focus on how the short-term changes in sex hormones during the menstrual cycle and the chronic changes with menopause affect the vascular system in women. Focus lies primarily on basal regulation of vascular tone and the role of physical activity on the blood vessels supplying skeletal muscle tissue. After a brief overview of the physiology and molecular mechanisms underlying regulation of vascular tone, the influence of sex hormones is briefly addressed. We then discuss the effect of exercise and exercise training on vascular function during acute and chronic changes in female sex hormones, with an emphasis on estrogen. The main focus of this review was on humans but includes data from studies on laboratory animals and cell culture where relevant.

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“…Some of the major mechanisms involved increased SIRT1, mitochondrial biogenesis, protection against oxidative stress and increased nitric oxide, all known to be involved in improved exercise performance. All of these mechanisms have been found to mediate enhanced exercise performance with chronic exercise training [2, 4, 8, 10–12, 29, 31, 32, 36]. …”

Section: Discussionmentioning

confidence: 99%

Disruption of adenylyl cyclase type 5 mimics exercise training

et al. 2017

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Exercise training is key to healthful longevity. Since exercise training compliance is difficult, it would be useful to have a therapeutic substitute that mimicked exercise training. We compared the effects of exercise training in wild type (WT) littermates with adenylyl cyclase type 5 knock out (AC5 KO) mice, a model of enhanced exercise performance. Exercise performance, measured by maximal distance and work to exhaustion, was increased in exercise trained WT to levels already attained in untrained AC5 KO. Exercise training in AC5 KO further enhanced their exercise performance. The key difference in untrained AC5 KO and exercise trained WT was the β-adrenergic receptor signaling, which was decreased in untrained AC5 KO compared to untrained WT but was increased in WT with exercise training. Despite this key difference, untrained AC5 KO and exercise trained WT mice shared similar gene expression, determined by deep sequencing, in their gastrocnemius muscle with 183 genes commonly up or down-regulated, mainly involving muscle contraction, metabolism and mitochondrial function. The SIRT1/PGC-1α pathway partially mediated the enhanced exercise in both AC5 KO and exercise trained WT mice, as reflected in the reduced exercise responses after administering a SIRT1 inhibitor, but did not abolish the enhanced exercise performance in the AC5 KO compared to untrained WT. Increasing oxidative stress with paraquat attenuated exercise performance more in untrained WT than untrained AC5 KO, reflecting the augmented oxidative stress protection in AC5 KO. Blocking nitric oxide actually reduced the enhanced exercise performance in untrained AC5 KO and trained WT to levels below untrained WT, demonstrating the importance of this mechanism. These results suggest that AC5 KO mice, without exercise training, share similar mechanisms responsible for enhanced exercise capacity with chronic exercise training, most importantly increased nitric oxide, and demonstrate more reserve with the addition of exercise training. A novel feature of the enhanced exercise performance in untrained AC5 KO mice is their decreased sympathetic tone, which is also beneficial to patients with cardiovascular disease.

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Aerobic Exercise Training Prevents the Onset of Endothelial Dysfunction via Increased Nitric Oxide Bioavailability and Reduced Reactive Oxygen Species in an Experimental Model of Menopause

Cited by 21 publications

References 47 publications

Evidence of microvascular dysfunction in patients with cystic fibrosis

Evidence of microvascular dysfunction in patients with cystic fibrosis

Limb vascular function in women-Effects of female sex hormones and physical activity

Disruption of adenylyl cyclase type 5 mimics exercise training

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