Hemorrhage at high altitude: impact of sustained hypobaric hypoxia on cerebral blood flow, tissue oxygenation, and tolerance to simulated hemorrhage in humans.

With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4 M) participated in LBNP protocols to presyncope at LA (1130 m) and 5-7 days following ascent to HA (3800 m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO2) through the ICA, and cerebral tissue oxygen saturation (ScO2) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304 s vs. HA: 1208 ± 306 s; P = 0.58). Overall, ICA blood flow and CDO2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P < 0.0001), but there was no effect of altitude on ScO2 responses (P = 0.59). Thus, sustained exposure to hypobaric hypoxia did not negatively impact tolerance to simulated hemorrhage. These data demonstrate the robustness of compensatory physiological mechanisms that preserve human cerebral blood flow and oxygen delivery during sustained hypoxia, ensuring cerebral tissue metabolism and neuronal function is maintained.

Neuroanatomical and neurophysiological evidence of pulmonary nociceptor and carotid chemoreceptor convergence in the nucleus tractus solitarius and nucleus ambiguus.

Pulmonary vagal nociceptors defend the airways. Cardiopulmonary vagal nociceptors synapse in the nucleus tractus solitarius (NTS). Evidence has demonstrated the convergence of cardiopulmonary nociceptors with afferents from carotid chemoreceptors. Whether sensory convergence occurs in motor nuclei and how sensory convergence affects reflexive efferent motor output directed toward the airways are critical knowledge gaps. Here, we show that distinct tracer injection into the pulmonary nociceptors and carotid chemoreceptors leads to co-labeled neurons in the nucleus tractus solitarius and nucleus ambiguus. Precise simultaneous stimulation delivered to pulmonary nociceptors and carotid chemoreceptors doubled efferent vagal output, enhanced phrenic pause, and subsequently augmented phrenic motor activity. These results suggest that multiple afferents are involved in protecting the airways and concurrent stimulation enhances airway defensive reflex output.NEW & NOTEWORTHY Sensory afferents have been shown to converge onto nucleus tractus solitarius primary neurons. Here, we show sensory convergence of two distinct sets of sensory afferents in motor nuclei of the nucleus ambiguus, which results in augmentation of airway defense motor output.

Duration at high altitude influences the onset of arrhythmogenesis during apnea.

PURPOSE: Autonomic control of the heart is balanced by sympathetic and parasympathetic inputs. Excitation of both sympathetic and parasympathetic systems occurs concurrently during certain perturbations such as hypoxia, which stimulate carotid chemoreflex to drive ventilation. It is well established that the chemoreflex becomes sensitized throughout hypoxic exposure; however, whether progressive sensitization alters cardiac autonomic activity remains unknown. We sought to determine the duration of hypoxic exposure at high altitude necessary to unmask cardiac arrhythmias during instances of voluntary apnea. METHODS: Measurements of steady-state chemoreflex drive (SS-CD), continuous electrocardiogram (ECG) and SpO2 (pulse oximetry) were collected in 22 participants on 1 day at low altitude (1045 m) and over eight consecutive days at high-altitude (3800 m). SS-CD was quantified as ventilation (L/min) over stimulus index (PETCO2/SpO2). RESULTS: Bradycardia during apnea was greater at high altitude compared to low altitude for all days (p < 0.001). Cardiac arrhythmias occurred during apnea each day but became most prevalent (> 50%) following Day 5 at high altitude. Changes in saturation during apnea and apnea duration did not affect the magnitude of bradycardia during apnea (ANCOVA; saturation, p = 0.15 and apnea duration, p = 0.988). Interestingly, the magnitude of bradycardia was correlated with the incidence of arrhythmia per day (r = 0.8; p = 0.004). CONCLUSION: Our findings suggest that persistent hypoxia gradually increases vagal tone with time, indicated by augmented bradycardia during apnea and progressively increased the incidence of arrhythmia at high altitude.

PKCε stimulation of TRPV1 orchestrates carotid body responses to asthmakines.

KEY POINTS: We have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats. Here, we show that pathophysiological concentrations of asthma-associated prototypical Th2 cytokines also stimulate the carotid bodies. Stimulation of the carotid bodies by these asthmakines involves a PKCε-transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites. As the carotid bodies' oxygen sensitivity is independent of PKCε-TRPV1 signalling, systemic blockade of PKCε may provide a novel therapeutic target to reduce allergen-induced asthmatic bronchoconstriction. Consistent with the therapeutic potential of blocking the PKCε-TRPV1 pathway, systemic delivery of a PKCε-blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin. ABSTRACT: The autonomic nervous system orchestrates organ-specific, systemic and behavioural responses to inflammation. Recently, we demonstrated a vital role for lysophosphatidic acid in stimulating the primary autonomic oxygen chemoreceptors, the carotid bodies, in parasympathetic-mediated asthmatic airway hyperresponsiveness. However, the cacophony of stimulatory factors and cellular mechanisms of carotid body activation are unknown. Therefore, we set out to determine the intracellular signalling involved in carotid body-mediated sensing of asthmatic blood-borne inflammatory mediators. We employed a range of in vitro and rat in situ preparations, site-directed mutagenesis, patch-clamp, nerve recordings and pharmacological inhibition to assess cellular signalling. We show that the carotid bodies are also sensitive to asthma-associated prototypical Th2 cytokines which elicit sensory nerve excitation. This provides additional asthmatic ligands contributing to the previously established reflex arc resulting in efferent vagal activity and asthmatic bronchoconstriction. This novel sensing role for the carotid body is mediated by a PKCε-dependent stimulation of transient receptor potential vanilloid 1 (TRPV1), likely via TRPV1 phosphorylation at sites T704 and S502. Importantly, carotid body oxygen sensing was unaffected by blocking either PKCε or TRPV1. Further, we demonstrate that systemic PKCε blockade reduces asthmatic respiratory distress in response to allergen and airway hyperresponsiveness. These discoveries support an inflammation-dependent, oxygen-independent function for the carotid body and suggest that targeting PKCε provides a novel therapeutic option to abate allergic airway disease without altering life-saving autonomic hypoxic reflexes.

Asthmatic allergen inhalation sensitises carotid bodies to lysophosphatidic acid.

The carotid bodies are multimodal sensors that regulate various autonomic reflexes. Recent evidence demonstrates their role in immune reflex regulation. Our previous studies using the allergen (ovalbumin) sensitised and exposed Brown Norway rat model of asthma suggest that carotid bodies mediate asthmatic bronchoconstriction through a lysophosphatidic acid (LPA) receptor (LPAr)-protein kinase C epsilon (PKCε)-transient receptor potential vanilloid one channel (TRPV1) pathway. Whilst naïve carotid bodies respond to LPA, whether their response to LPA is enhanced in asthma is unknown. Here, we show that asthmatic sensitisation of Brown Norway rats involving repeated aerosolised allergen challenges over 6 days, results in an augmentation of the carotid bodies' acute sensitivity to LPA. Increased expression of LPAr in the carotid bodies and petrosal ganglia likely contributed to this sensitivity. Importantly, allergen sensitisation of the carotid bodies to LPA did not alter their hypoxic response, nor did hypoxia augment LPA sensitivity acutely. Our data demonstrate the ability of allergens to sensitise the carotid bodies, highlighting the likely role of the carotid bodies and blood-borne inflammatory mediators in asthma.

Hindlimb unweighting does not alter vasoconstrictor responsiveness and nitric oxide-mediated inhibition of sympathetic vasoconstriction.

KEY POINTS: Physical inactivity increases the risk of cardiovascular disease and may alter sympathetic nervous system control of vascular resistance. Hindlimb unweighting (HU), a rodent model of physical inactivity, has been shown to diminish sympathetic vasoconstrictor responsiveness and reduce NO synthase expression in isolated skeletal muscle blood vessels. Our understanding of the effects of HU on sympathetic vascular regulation in vivo is very limited. The present findings demonstrate that HU did not alter sympathetic vasoconstrictor responsiveness and NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. This study suggests that short-term physical inactivity does not alter in vivo sympathetic vascular control in the skeletal muscle vascular bed at rest and during contraction. ABSTRACT: We tested the hypothesis that physical inactivity would increase sympathetic vasoconstrictor responsiveness and diminish NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague-Dawley rats (n = 33) were randomly assigned to sedentary time control (S) or hindlimb unweighted (HU) groups for 21 days. Following the intervention, rats were anaesthetized and instrumented for measurement of arterial blood pressure and femoral artery blood flow and stimulation of the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulation delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after NO synthase blockade with l-NAME (5 mg kg i.v.). Sympathetic vasoconstrictor responsiveness was not different (P > 0.05) in S and HU rats at rest (S, 2 Hz, -26 ± 8% and 5 Hz, -46 ± 12%; and HU, 2 Hz, -29 ± 9% and 5 Hz, -51 ± 10%) and during contraction (S, 2 Hz, -10 ± 7% and 5 Hz, -23 ± 11%; and HU, 2 Hz, -9 ± 5% and 5 Hz, -22 ± 7%). Nitric oxide synthase blockade caused a similar increase (P > 0.05) in sympathetic vasoconstrictor responsiveness in HU and S rats at rest (S, 2 Hz, -41 ± 7% and 5 Hz, -58 ± 8%; and HU, 2 Hz, -43 ± 6% and 5 Hz, -63 ± 8%) and during muscle contraction (S, 2 Hz, -15 ± 6% and 5 Hz, -31 ± 11%; and HU, 2 Hz, -12 ± 5% and 5 Hz, -29 ± 8%). Skeletal muscle NO synthase expression and ACh-mediated vasodilatation were also not different between HU and S rats. These data suggest that HU does not alter sympathetic vasoconstrictor responsiveness and NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle.

Exercise training augments neuronal nitric oxide synthase-mediated inhibition of sympathetic vasoconstriction in contracting skeletal muscle of rats.

We tested the hypothesis that exercise training would increase neuronal nitric oxide synthase (nNOS)-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague-Dawley rats (n = 18) were randomized to sedentary or exercise-trained (40 m min(-1), 5° grade; 5 days week(-1) for 4 weeks) groups. Following completion of sedentary behaviour or exercise training, rats were anaesthetized and instrumented with a brachial artery catheter, femoral artery flow probe and stimulating electrodes on the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulations delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg kg(-1), i.v.) and subsequent non-selective NOS blockade with l-NAME (5 mg kg(-1), i.v.; SMTC + l-NAME). At rest, sympathetic vasoconstrictor responsiveness was greater (P < 0.05) in exercise-trained compared to sedentary rats in control, SMTC and SMTC + l-NAME conditions. During contraction, the constrictor response was not different (P > 0.05) between exercise trained (2 Hz: -11 ± 4%FVC; 5 Hz: -21 ± 5%FVC) and sedentary rats (2 Hz: -7 ± 6%FVC; 5 Hz: -18 ± 10%FVC) in control conditions. SMTC augmented (P < 0.05) sympathetic vasoconstriction in sedentary and exercise-trained rats; however, sympathetic vasoconstrictor responsiveness was greater (P < 0.05) in exercise-trained (2 Hz: -27 ± 5%FVC; 5 Hz: -39 ± 5%FVC) compared to sedentary (2 Hz: -17 ± 6%FVC; 5 Hz: -27 ± 8%FVC) rats during selective nNOS inhibition. SMTC + l-NAME further augmented (P < 0.05) sympathetic vasoconstrictor responsiveness by a similar magnitude (P > 0.05) in exercise-trained and sedentary rats. These data demonstrate that exercise training augmented nNOS-mediated inhibition of sympathetic vasoconstriction in contracting muscle.

Sensory neurons regulate stimulus-dependent humoral immunity.

Sensory neurons sense pathogenic infiltration, serving to inform immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides which specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and/or aggravated humoral immunity.

Sensory neurons regulate stimulus-dependent humoral immunity in mouse models of bacterial infection and asthma.

Sensory neurons sense pathogenic infiltration to drive innate immune responses, but their role in humoral immunity is unclear. Here, using mouse models of Streptococcus pneumoniae infection and Alternaria alternata asthma, we show that sensory neurons are required for B cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion increases bacterial burden and reduces B cell numbers, IgG release, and neutrophil stimulation. Meanwhile, during A. alternata-induced airway inflammation, sensory neuron depletion decreases B cell population sizes, IgE levels, and asthmatic characteristics. Mechanistically, during bacterial infection, sensory neurons preferentially release vasoactive intestinal polypeptide (VIP). In response to asthma, sensory neurons release substance P. Administration of VIP into sensory neuron-depleted mice suppresses bacterial burden, while VIPR1 deficiency increases infection. Similarly, exogenous substance P delivery aggravates asthma in sensory neuron-depleted mice, while substance P deficiency ameliorates asthma. Our data, thus demonstrate that sensory neurons release select neuropeptides which target B cells dependent on the immunogen.

Epigenetic upregulation of carotid body angiotensin signaling increases blood pressure.

Epigenetic changes can be shaped by a wide array of environmental cues as well as maternal health and behaviors. One of the most detrimental behaviors to the developing fetus is nicotine exposure. Perinatal nicotine exposure remains a significant risk factor for cardiovascular health and in particular, hypertension. Increased basal carotid body activity and excitation are significant contributors to hypertension. This study investigated the epigenetic changes to carotid body activity induced by perinatal nicotine exposure resulting in carotid body-mediated hypertension. Using a rodent model of perinatal nicotine exposure, we show that angiotensin II type 1 receptor is upregulated in the carotid bodies of nicotine-exposed offspring. These changes were attributed to an upregulation of genetic promotion as DNA methylation of angiotensin II type 1 receptor occurred within intron regions, exemplifying an upregulation of genetic transcription for these genes. Nicotine increased angiotensin signaling in vitro . Carotid body reactivity to angiotensin was increased in perinatal nicotine-exposed offspring compared to control offspring. Further, carotid body denervation reduced arterial pressure as a result of suppressed efferent sympathetic activity in perinatal nicotine-exposed offspring. Our data demonstrate that perinatal nicotine exposure adversely affects carotid body afferent sensing, which augments efferent sympathetic activity to increase vasoconstrictor signaling and induce hypertension. Targeting angiotensin signaling in the carotid bodies may provide a way to alleviate hypertension acquired by adverse maternal uterine environments in general and perinatal nicotine exposure in particular.

Non-canonical IL-22 receptor signaling remodels the mucosal barrier during fungal immunosurveillance.

Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.

Short-term exercise training augments 2-adrenoreceptor-mediated sympathetic vasoconstriction in resting and contracting skeletal muscle.

We hypothesized that exercise training (ET) would alter α2-adrenoreceptor-mediated sympathetic vasoconstriction. Sprague-Dawley rats (n = 30) were randomized to sedentary (S), mild- (M) or heavy-intensity (H) treadmill ET groups (5 days per week for 4 weeks). Following the ET component of the study, rats were anaesthetized, and instrumented for lumbar sympathetic chain stimulation, triceps surae muscle contraction and measurement of femoral vascular conductance (FVC). The percentage change of FVC in response to sympathetic stimulation was determined at rest and during contraction in control, α2 blockade (yohimbine) and combined α2 + nitric oxide (NO) synthase (NOS) blockade (N-nitro-L-arginine methyl ester hydrochloride, L-NAME) conditions. ET augmented (P < 0.05) sympathetic vasoconstrictor responses at rest and during contraction. Yohimbine reduced (P < 0.05) the vasoconstrictor response in ET rats at rest (M: 2 Hz: 8 ± 2%, 5 Hz: 9 ± 4%; H: 2 Hz: 14 ± 5%, 5 Hz: 11 ± 6%) and during contraction (M: 2 Hz: 9 ± 2%, 5 Hz: 9 ± 5%; H: 2 Hz: 8 ± 3%, 5 Hz: 6 ± 6%) but did not change the response in S rats. The addition of L-NAME caused a larger increase (P < 0.05) in the vasoconstrictor response in ET than in S rats at rest (2 Hz: S: 8 ± 2%, M: 15 ± 3%, H: 23 ± 7%; 5 Hz: S: 8 ± 5%, M: 15 ± 3%, H: 17 ± 5%) and during contraction (2 Hz: S: 9 ± 3%, M: 18 ± 3%, H: 22 ± 6%; 5 Hz: S: 9 ± 5%, M: 22 ± 4%, H:26 ± 9%). Sympatholysis was greater (P < 0.05) in ET than in S rats. Blockade of α2-adrenoreceptors and NOS reduced (P < 0.05) sympatholysis in ET rats, but had no effect on sympatholysis in S rats. In conclusion, ET increased α2-mediated vasoconstriction at rest and during contraction.

Short-term exercise training enhances functional sympatholysis through a nitric oxide-dependent mechanism.

We tested the hypothesis that short-term mild- (M) and heavy-intensity (H) exercise training would enhance sympatholysis through a nitric oxide (NO)-dependent mechanism. Sprague-Dawley rats (n = 36) were randomly assigned to sedentary (S) or to M (20 m min(-1) 5% gradient) or H exercise training groups (40 m min(-1) 5% gradient). Rats assigned to M and H groups trained on 5 days week(-1) for 4 weeks, with the volume of training being matched between groups. Rats were anaesthetized and instrumented for stimulation of the lumbar sympathetic chain and the measurement of arterial blood pressure and femoral artery blood flow. The triceps surae muscle group was stimulated to contract rhythmically at 30 and 60% of maximal contractile force (MCF). The percentage change of femoral vascular conductance (%FVC) in response to sympathetic stimulation delivered at 2 and 5 Hz was determined at rest and during contraction at 30 and 60% MCF. The vascular response to sympathetic stimulation was reduced as a function of MCF in all rats (P < 0.05). At 30% MCF, the magnitude of sympatholysis (%FVC rest - contraction; %FVC) was greater in H compared with M and S groups (%FVC at 2 Hz, S, 9 ± 5; M, 11 ± 8; and H, 18 ± 7; and %FVC at 5 Hz, S, 6 ± 6; M, 12 ± 9; and H, 18 ± 7; P < 0.05) and was greater in H and M compared with S at 60% MCF (%FVC at 2 Hz, S, 15 ± 5; M, 25 ± 3; and H, 36 ± 6; and %FVC at 5 Hz, S, 22 ± 6; M, 33 ± 9; and H, 39 ± 9; P < 0.05). Blockade of NO synthase did not alter the magnitude of sympatholysis in S during contraction at 30 or 60% MCF. In contrast, NO synthase inhibition diminished sympatholysis in H at 30% MCF and in M and H at 60% MCF (P < 0.05). The present findings indicate that short-term exercise training augments sympatholysis in a training-intensity-dependent manner and through an NO-dependent mechanism.

Pathogen recognition by sensory neurons: hypotheses on the specificity of sensory neuron signaling.

Sensory neurons cooperate with barrier tissues and resident immune cells to form a significant aspect of defensive strategies in concert with the immune system. This assembly of neuroimmune cellular units is exemplified across evolution from early metazoans to mammalian life. As such, sensory neurons possess the capability to detect pathogenic infiltrates at barrier surfaces. This capacity relies on mechanisms that unleash specific cell signaling, trafficking and defensive reflexes. These pathways exploit mechanisms to amplify and enhance the alerting response should pathogenic infiltration seep into other tissue compartments and/or systemic circulation. Here we explore two hypotheses: 1) that sensory neurons' potential cellular signaling pathways require the interaction of pathogen recognition receptors and ion channels specific to sensory neurons and; 2) mechanisms which amplify these sensing pathways require activation of multiple sensory neuron sites. Where possible, we provide references to other apt reviews which provide the reader more detail on specific aspects of the perspectives provided here.

Sex-related Differences in Loop Gain during High-Altitude Sleep-disordered Breathing.

Rationale: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P < 0.0001) altitude. The change in REI per change in LGn was significantly greater in men than in women (107 ± 46 events/h/LGn; P = 0.02). Conclusions: The LGn response to high altitude differed between sexes and contributed to worsening of CSA over time in men but not in women. This sex difference in acclimatization appears to protect females from high altitude-related CSA. These data provide fundamental sex-specific physiological insight into high-altitude acclimatization in healthy individuals and may help to inform sex differences in sleep-disordered breathing pathogenesis in patients with cardiorespiratory disease.

Short-term exercise training augments sympathetic vasoconstrictor responsiveness and endothelium-dependent vasodilation in resting skeletal muscle.

We tested the hypotheses that 4 wk of exercise training would diminish the magnitude of vasoconstriction in response to sympathetic nerve stimulation and augment endothelium-dependent vasodilation (EDD) in resting skeletal muscle in a training intensity-dependent manner. Sprague-Dawley rats were randomly assigned to sedentary time-control (S), mild- (M; 20 m/min, 5% grade), or heavy-intensity (H; 40 m/min, 5% grade) treadmill exercise groups. Animals trained 5 days/wk for 4 wk with training volume matched between groups. Rats were anesthetized and instrumented for study 24 h after the last training session. Arterial pressure and femoral artery blood flow were measured, and femoral vascular conductance (FVC) was calculated. Lumbar sympathetic chain stimulation was delivered continuously at 2 Hz and in patterns at 20 and 40 Hz. EDD was assessed by the vascular response to intra-arterial bolus injections of ACh. The response (% change FVC) to sympathetic stimulation increased (P < 0.05) in a training intensity-dependent manner at 2 Hz (S: -20.2 ± 9.8%, M: -34.0 ± 6.7%, and H: -44.9 ± 2.0%), 20 Hz (S: -22.0 ± 10.6%, M: -31.2 ± 8.4%, and H: -42.8 ± 5.9%), and 40 Hz (S: H -24.5 ± 8.5%, M: -35.1 ± 8.9%, H: -44.9 ± 6.5%). The magnitude of EDD also increased in a training intensity-dependent manner (P < 0.05). These data demonstrate that short-term exercise training augments the magnitude of vasoconstriction in response to sympathetic stimulation and EDD in resting skeletal muscle in a training intensity-dependent manner.

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis.

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. The ß-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that EphA2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 restrains IL-23 secretion from and migration of dendritic cells. IL-23 signaling prevents ferroptotic host cell death during infection to limit inflammation and immunopathology. Further, host cell ferroptosis limits antifungal effector functions via releasing the lipid peroxidation product 4-hydroxynonenal to induce various forms of cell death. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

Functional optical coherence tomography at altitude: retinal microvascular perfusion and retinal thickness at 3,800 meters.

Cerebral hypoxia is a serious consequence of several cardiorespiratory illnesses. Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into cerebral hypoxia in critical illness. In addition, although sex-specific differences in cardiovascular diseases are strongly supported, few have focused on differences in ocular blood flow. We evaluated the retinal microvasculature in males (n = 11) and females (n = 7) using functional optical coherence tomography at baseline (1,130 m) (day 0), following rapid ascent (day 2), and prolonged exposure (day 9) to high altitude (3,800 m). Retinal vascular perfusion density (rVPD; an index of total blood supply), retinal thickness (RT; reflecting vascular and neural tissue volume), and arterial blood were acquired. As a group, rVPD increased on day 2 versus day 0 (P < 0.001) and was inversely related to [Formula: see text] (R2 = 0.45; P = 0.006). By day 9, rVPD recovered to baseline but was significantly lower in males than in females (P = 0.007). RT was not different on day 2 versus day 0 (P > 0.99) but was reduced by day 9 relative to day 0 and day 2 (P < 0.001). RT changes relative to day 0 were inversely related to changes in [Formula: see text] on day 2 (R2 = 0.6; P = 0.001) and day 9 (R2 = 0.4; P = 0.02). RT did not differ between sexes. These data suggest differential time course and regulation of the retina during rapid ascent and prolonged exposure to high altitude and are the first to demonstrate sex-specific differences in rVPD at high altitude. The ability to assess intact microvasculature contiguous with the brain has widespread research and clinical applications.NEW & NOTEWORTHY Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into consequence of cerebral hypoxia in critical illness. This study demonstrates dynamic regulation of the retina during rapid ascent and prolonged exposure to high altitude and is the first to demonstrate sex-specific differences in retinal microvasculature at high altitude. The ability to dynamically assess intact microvasculature contiguous with the brain has widespread research and clinical applications.