Chronic mountain sickness (CMS), originally characterized by excess hemoglobin (Hb), is currently diagnosed using score-based diagnostic criteria combined with excessive erythrocytosis and clinical symptoms. However, the current criteria have limited applicability. We applied these criteria to 1,029 Chinese Han males migrated to and have been stayed at the Qinghai-Tibet plateau (3,700–5,000 m) for 2–96 months to investigate the prevalence of CMS and its correlations with Hb concentration, altitude, and the length of residence.

Background: Stromal interaction molecule 1 (STIM1) is a newly discovered Ca²⁺ sensor on the endoplasmic reticulum which is an indispensable part in the activation of store-operated Ca²⁺ channels (SOC). Recent studies demonstrate that SOC of pulmonary smooth muscle cells (PASMCs) were upregulated by chronic hypoxia which contribute to the enhanced pulmonary vasoconstriction and vascular remodeling. However, the exact role of STIM1 in the development of chronic hypoxic pulmonary hypertension(HPH) remains unclear. Methods: In this study we investigated the cellular distribution and expression of STIM1 by immunofluorescence, qRTPCR and Western blotting methods in Wistar rat distal intrapulmonary arteries under normal and chronic hypobaric hypoxic conditions. In vitro, Wistar rat PASMCs were isolated and cultured. PASMCs were transfected with siRNA targeting STIM1 gene by liposome. The expression of STIM1 protein was detected by Western blotting. [³H]-thymidine ([³H]-TdR) incorporation were performed to detect PASMCs proliferation. The cell cycle was analyzed by flow cytometry. The SOC-mediated Ca²⁺ influx was calculated by Ca²⁺ fluorescence imaging and the nuclear translocation of NFATc3 was determined by immunofluorescence and Western blot analysis of nuclear extracts. Results: We found that during the development of HPH and the initiation of vascular remodeling, the mRNA and protein expression levels of STIM1 significantly increased in the distal intrapulmonary arteries. Moderate hypoxia significantly promotes PASMCs proliferation and cell cycle progression. Silencing of STIM1 significantly decreased cellular proliferation and delayed the cell cycle progression induced by hypoxia. Silencing of STIM1 also significantly decreased SOC-mediated Ca²⁺ influx and inhibited the nuclear translocation of NFATc3 in hypoxic PASMCs. Conclusion: Our findings suggest that chronic hypobaric hypoxia upregulates the expression of STIM1 in the distal intrapulmonary arteries which plays an important role in the hypoxia-induced PASMCs proliferation via SOC/Ca²⁺/NFAT pathway and may represent a novel therapeutic target for the prevention of hypoxia pulmonary hypertension.

Introduction: Inadequate oxygen availability may lead to impairment of neurocognitive functions. The aim of the present study was to investigate the effect of acute high‐altitude exposure on the cerebral hemodynamic response and working memory.Methods: The same subjects performed working memory exercises with forward and backward digit span tasks both under normal oxygen conditions and in large simulated hypobaric hypoxia chambers, and a series of physiological parameters were evaluated. Functional near‐infrared spectroscopy was used to measure cerebral blood flow changes in the dorsolateral prefrontal cortex (DLPFC) during the tasks.Results: Compared with normoxic conditions, under hypoxic conditions, the heart rate and blood pressure increased, blood oxygen saturation decreased significantly, and the forward task had similar accuracy and response time, while the backward task had lower accuracy and longer response time. Neuroimaging analysis showed increased activation in the DLPFC during the forward task and deactivation during the backward task under hypobaric hypoxia conditions.Conclusion: Acute high‐altitude exposure leads to physiological adaptations. The abnormal hemodynamic responses of the DLPFC to hypoxia at low pressure reveal the disruption of neurocognitive function by acute high‐altitude exposure, which compromises complex cognitive functions, and provides a promising application for functional near infrared spectroscopy in the exploration of neural mechanisms in the brain during high‐altitude exposure.

Acute mountain sickness (AMS) is a major health issue for people travelling to high altitudes. This study was designed to comprehensively evaluate the changes in clinical characteristics and biochemical indices of high-altitude travelers and determine whether these changes were associated with AMS. A total of 14 clinical indices and 52 biochemical indices were determined in 22 subjects before and during acute high-altitude exposure. Six hours after passive ascent to 3648 m (Lhasa, China), the Lake Louise Scoring (LLS) system 2018 was used to assess AMS, which was defined as headache with a total LLS ≥3. Before travelling to high altitudes, uric acid (UA), platelet distribution width (PDW), mitral peak E velocity (MVE), and ejection fraction (EF) were significantly higher in AMS-resistant individuals than in AMS-susceptible ones (all p < 0.05). A good predictive value of UA (0.817, 95% CI: 0.607-1.000) and PDW (0.844, 95% CI: 0.646-1.000) for AMS-susceptible subjects was found. With high-altitude experience, 14 subjects were diagnosed as having AMS. Compared with non-AMS, the changes in UA and number of neutrophils in AMS presented a significant difference (all p < 0.05). The high-altitude-induced changes in UA, area under the curve, specificity, and sensitivity for identifying AMS were 0.883 (95% CI: 0.738-1.000), 83.30%, and 90.00%, respectively. Human presents a compensatory physiological and biochemical response to high-altitude travel at early phase. The UA concentration before travel and its trend with high-altitude experience exhibited good performance for identifying AMS.

Background: The modulation of arachidonic acid (AA) metabolism pathway is identified in metabolic alterations after hypoxia exposure, but its biological function is controversial. We aimed at integrating plasma metabolomic and transcriptomic approaches to systematically explore the roles of the AA metabolism pathway in response to acute hypoxia using an acute mountain sickness (AMS) model. Methods: Blood samples were obtained from 53 enrolled subjects before and after exposure to high altitude. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and RNA sequencing were separately performed for metabolomic and transcriptomic profiling, respectively. Influential modules comprising essential metabolites and genes were identified by weighted gene co-expression network analysis (WGCNA) after integrating metabolic information with phenotypic and transcriptomic datasets, respectively. Results: Enrolled subjects exhibited diverse response manners to hypoxia. Combined with obviously altered heart rate, oxygen saturation, hemoglobin, and Lake Louise Score (LLS), metabolomic profiling detected that 36 metabolites were highly related to clinical features in hypoxia responses, out of which 27 were upregulated and nine were downregulated, and could be mapped to AA metabolism pathway significantly. Integrated analysis of metabolomic and transcriptomic data revealed that these dominant molecules showed remarkable association with genes in gas transport incapacitation and disorders of hemoglobin metabolism pathways, such as ALAS2, HEMGN. After detailed description of AA metabolism pathway, we found that the molecules of 15-d-PGJ2, PGA2, PGE2, 12-O-3-OH-LTB4, LTD4, LTE4 were significantly up-regulated after hypoxia stimuli, and increased in those with poor response manner to hypoxia particularly. Further analysis in another cohort showed that genes in AA metabolism pathway such as PTGES, PTGS1, GGT1, TBAS1 et al. were excessively elevated in subjects in maladaptation to hypoxia. Conclusion: This is the first study to construct the map of AA metabolism pathway in response to hypoxia and reveal the crosstalk between phenotypic variation under hypoxia and the AA metabolism pathway. These findings may improve our understanding of the advanced pathophysiological mechanisms in acute hypoxic diseases and provide new insights into critical roles of the AA metabolism pathway in the development and prevention of these diseases.

Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca²⁺(Ca²⁺_m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP₃R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP₃R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca²⁺_m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP₃R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP₃R3 phosphorylation, which contribute to the decrease of Ca²⁺_m and mitochondrial impairment.