Contributions of sex to cerebrovascular function and pathology

Robison, Lisa S.; Gannon, Olivia J.; Salinero, Abigail E.; Zuloaga, Kristen L.

doi:10.1016/j.brainres.2018.12.030

Cited by 90 publications

(88 citation statements)

References 312 publications

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“…Nearly one‐half of postmenopausal women develop osteoporosis, but menopause also increases incidence of other comorbidities including coronary artery disease, certain cancers, chronic obstructive pulmonary disease, stroke, and dementia . It is tempting to speculate that the proinflammatory T cells produced by E 2 loss also contribute to the pathogenesis of these conditions because all these conditions are known to be caused by both chronic inflammation and metabolic syndrome . In conclusion, our studies establish a new regulatory circuit between E 2 , the immune system, and the skeletal system.…”

Section: Discussionmentioning

confidence: 69%

Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

Cline-Smith

Axelbaum

Shashkova

et al. 2020

Journal of Bone and Mineral Research

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The loss of estrogen (E2) initiates a rapid phase of bone loss leading to osteoporosis in one‐half of postmenopausal women, but the mechanism is not fully understood. Here, we show for the first time how loss of E2 activates low‐grade inflammation to promote the acute phase of bone catabolic activity in ovariectomized (OVX) mice. E2 regulates the abundance of dendritic cells (DCs) that express IL‐7 and IL‐15 by inducing the Fas ligand (FasL) and apoptosis of the DC. In the absence of E2, DCs become long‐lived, leading to increased IL‐7 and IL‐15. We find that IL‐7 and IL‐15 together, but not alone, induced antigen‐independent production of IL‐17A and TNFα in a subset of memory T cells (TMEM). OVX of mice with T‐cell–specific ablation of IL15RA showed no IL‐17A and TNFα expression, and no increase in bone resorption or bone loss, confirming the role of IL‐15 in activating the TMEM and the need for inflammation. Our results provide a new mechanism by which E2 regulates the immune system, and how menopause leads to osteoporosis. The low‐grade inflammation is likely to cause or contribute to other comorbidities observed postmenopause. © 2020 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 69%

Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

Cline-Smith

Axelbaum

Shashkova

et al. 2020

Journal of Bone and Mineral Research

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“…45 Estradiol has also been shown to protect against cognitive impairment in young male VCID rats, 28 but has not been tested in females. While estradiol has a variety of protective effects on the brain, 37,38 it is important to note that protection is likely dependent on the timing of administration in postmenopausal women (<5 yrs from menopause onset), formulation (17β-estradiol), and duration. 46,47 In line with our current results, there is clinical evidence that obesity and prediabetes both have significant links to VCID.…”

Section: Discussionmentioning

confidence: 99%

Sex‐specific effects of high‐fat diet on cognitive impairment in a mouse model of VCID

et al. 2020

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Half of all dementia patients have evidence of vascular contributions to cognitive impairment and dementia (VCID), either as a single pathology or as a multi-etiology dementia, 1 yet, there remains a severe lack of knowledge regarding VCID. Type 2 diabetes is a major risk factor for VCID, as it is known to cause damage to the cerebral vasculature and blood brain barrier (BBB). 2-4 Furthermore, there is a sex difference in risk for VCID that varies by metabolic status. While most studies agree that in a nondiabetic population, VCID risk is slightly higher in men than in women (under the age of 90), 5 in a pooled analysis of 2.3 million individuals, it was found

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“…This may also explain why previous studies with no such pre‐screening have experienced greater decrements in performance at lower levels of hypoxia. Finally, considering the influence of sex on cerebral function (Robison, Gannon, Salinero, & Zuloaga, ), it is necessary for future studies to confirm these findings in females.…”

Section: Discussionmentioning

confidence: 99%

Cognitive performance is associated with cerebral oxygenation and peripheral oxygen saturation, but not plasma catecholamines, during graded normobaric hypoxia

Williams

Corbett

McMorris

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?What are the mechanisms responsible for the decline in cognitive performance following exposure to acute normobaric hypoxia? What are the main findings and their importance?We found that (1) performance of a complex central executive task (n‐back) was reduced at FnormalIO2 0.12; (2) there was a strong correlation between performance of the n‐back task and reductions in SnormalpO2 and cerebral oxygenation; and (3) plasma adrenaline, noradrenaline, cortisol and copeptin were not correlated with cognitive performance. Abstract It is well established that hypoxia impairs cognitive function; however, the physiological mechanisms responsible for these effects have received relatively little attention. This study examined the effects of graded reductions in fraction of inspired oxygen (FnormalIO2) on oxygen saturation (SnormalpO2), cerebral oxygenation, cardiorespiratory variables, activity of the sympathoadrenal system (adrenaline, noradrenaline) and hypothalamic–pituitary–adrenal axis (cortisol, copeptin), and cognitive performance. Twelve healthy males [mean (SD), age: 22 (4) years, height: 178 (5) cm, mass: 75 (9) kg, FEV1/FVC ratio: 85 (5)%] completed a four‐task battery of cognitive tests to examine inhibition, selective attention (Eriksen flanker), executive function (n‐back) and simple and choice reaction time (Deary–Liewald). Tests were completed before and following 60 min of exposure to FnormalIO2 0.2093, 0.17, 0.145 and 0.12. Following 60 min of exposure, response accuracy in the n‐back task was significantly reduced in FnormalIO2 0.12 compared to baseline [82 (9) vs. 93 (5)%; P < 0.001] and compared to all other conditions at the same time point [FnormalIO2 0.2093: 92 (3)%; FnormalIO2 0.17: 91 (6)%; FnormalIO2 0.145: 85 (10)%; FnormalIO2 12: 82 (9)%; all P < 0.05]. The performance of the other tasks was maintained. Δaccuracy and Δreaction time of the n‐back task was correlated with both ΔSnormalpO2 [r(9) = 0.66, P < 0.001 and r(9) = −0.36, P = 0.037, respectively] and Δcerebral oxygenation [r(7) = 0.55, P < 0.001 and r(7) = −0.38, P = 0.045, respectively]. Plasma adrenaline, noradrenaline, cortisol and copeptin were not significantly elevated in any condition or correlated with any of the tests of cognitive performance. These findings suggest that reductions in peripheral oxygen saturation and cerebral oxygenation, and not increased activity of the sympathoadrenal system and hypothalamic–pituitary–adrenal axis, as previously speculated, are responsible for a decrease in cognitive performance during normobaric hypoxia.

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Contributions of sex to cerebrovascular function and pathology

Cited by 90 publications

References 312 publications

Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

Sex‐specific effects of high‐fat diet on cognitive impairment in a mouse model of VCID

Cognitive performance is associated with cerebral oxygenation and peripheral oxygen saturation, but not plasma catecholamines, during graded normobaric hypoxia

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