Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50-70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex is also an important risk factor. Sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions. An understudied sex hormone receptor that can induce activation of oxidative stress signaling is the membrane androgen receptor (mAR). mAR can mediate NADPH oxidase (NOX) generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer’s disease. Further complicating this is that aging can alter sex hormone signaling. Prior to menopause, women experience more estrogens than androgens. During menopause, this sex hormone profile switches in women due to the dramatic ovarian loss of 17β-estradiol with maintained ovarian androgen (testosterone, androstenedione) production. Indeed, aging men have higher estrogens than aging women due to aromatization of androgens to estrogens. Therefore, higher activation of mAR-NOX signaling could occur in menopausal women compared to aged men, mediating the observed sex differences. Understanding these signaling cascades could provide therapeutic targets for neurodegenerative diseases.

Reperfusion that follows a period of ischaemia paradoxically reduces vasodilator function in humans and contributes to the tissue damage associated with an ischaemic event. Acute wholebody hot water immersion protects against vascular ischaemia-reperfusion (I-R) injury in young healthy humans. However, the effect of acute lower leg heating on I-R injury is unclear. Therefore, wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:302-311.

There is a sustained reduction in arterial blood pressure that occurs in aged adults following exposure to acute leg heating. However, the neurovascular mechanisms mediating this response remain unknown. Our findings demonstrate for the first time that this reduction in arterial blood pressure is mediated, in part, by a sympathoinhibitory effect that alters the compensatory neural response to hypotension in aged adults.

Background Hypoxia is associated with pregnancy complications, such as preeclampsia, placental abruption, and gestational sleep apnea. Hypoxic insults during gestation can impact the brain maturation of cortical and subcortical pathways, such as the nigrostriatal pathway. However, the long-term effects of in utero hypoxic stress exposure on brain maturation in offspring are unclear, especially exposure during late gestation. The purpose of this study was to determine the impact of gestational hypoxia in late pregnancy on developmental programming of subcortical brain maturation by focusing on the nigrostriatal pathway. Methods Timed pregnant Long–Evans rats were exposed to chronic intermittent hypoxia or room air normoxia from gestational day (GD) 15–19 (term 22–23 days). Male and female offspring were assessed during two critical periods: puberty from postnatal day (PND) 40–45 or young adulthood (PND 60–65). Brain maturation was quantified by examining (1) the structural development of the nigrostriatal pathway via analysis of locomotor behaviors and the substantia nigra dopaminergic neuronal cell bodies and (2) the refinement of the nigrostriatal pathway by quantifying ultrasonic vocalizations (USVs). Results The major findings of this study are gestational hypoxia has age- and sex-dependent effects on subcortical brain maturation in offspring by adversely impacting the refinement of the nigrostriatal pathway in the absence of any effects on the structural development of the pathway. During puberty, female offspring were impacted more than male offspring, as evidenced by decreased USV call frequency, chirp USV call duration, and simple call frequency. In contrast, male offspring were impacted more than female offspring during young adulthood, as evidenced by increased latency to first USV, decreased simple USV call intensity, and increased harmonic USV call bandwidth. No effects of gestational hypoxia on the structural development of the nigrostriatal pathway were observed. Conclusions These novel findings demonstrate hypoxic insults during pregnancy mediate developmental programming of the cortical and subcortical pathways, in which male offspring exhibit long-term adverse effects compared to female offspring. Impairment of cortical and subcortical pathways maturation, such as the nigrostriatal pathway, may increase risk for neuropsychiatric disorders (e.g., mood disorders, cognitive dysfunction, brain connectivity dysfunction).