Identification of blood exosomal metabolomic profiling for high-altitude cerebral edema.

High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC‒MS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5'-monophosphate, deoxyguanosine 5'-monophosphate, guanosine, and hypoxanthine-9-ß-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-ß-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5'-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.

Wilderness Medical Society Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment of Acute Altitude Illness: 2024 Update.

To provide guidance to clinicians about best practices, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for prevention, diagnosis, and treatment of acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. Recommendations are graded based on the quality of supporting evidence and the balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches for managing each form of acute altitude illness that incorporate these recommendations as well as recommendations on how to approach high altitude travel following COVID-19 infection. This is an updated version of the original WMS Consensus Guidelines for the Prevention and Treatment of Acute Altitude Illness published in Wilderness & Environmental Medicine in 2010 and the subsequently updated WMS Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness published in 2014 and 2019.

Isolated high altitude psychosis, delirium at high altitude, and high altitude cerebral edema: are these diagnoses valid?

Psychosis is a psychopathological syndrome that can be triggered or caused by exposure to high altitude (HA). Psychosis can occur alone as isolated HA psychosis or can be associated with other mental and often also somatic symptoms as a feature of delirium. Psychosis can also occur as a symptom of high altitude cerebral edema (HACE), a life-threatening condition. It is unclear how psychotic symptoms at HA should be classified into existing diagnostic categories of the most widely used classification systems of mental disorders, including the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and the International Statistical Classification of Diseases and Related Health Problems (ICD-11). We provide a diagnostic framework for classifying symptoms using the existing diagnostic categories: psychotic condition due to a general medical condition, brief psychotic disorder, delirium, and HACE. We also discuss the potential classification of isolated HA psychosis into those categories. A valid and reproducible classification of symptoms is essential for communication among professionals, ensuring that patients receive optimal treatment, planning further trips to HA for individuals who have experienced psychosis at HA, and advancing research in the field.

Progress in the Treatment of High Altitude Cerebral Edema: Targeting REDOX Homeostasis.

With the increasing of altitude activities from low-altitude people, the study of high altitude cerebral edema (HACE) has been revived. HACE is a severe acute mountain sickness associated with exposure to hypobaric hypoxia at high altitude, often characterized by disturbance of consciousness and ataxia. As for the pathogenesis of HACE, previous studies suggested that it might be related to the disorder of cerebral blood flow, the destruction of blood-brain barrier and the injury of brain parenchyma cells caused by inflammatory factors. In recent years, studies have confirmed that the imbalance of REDOX homeostasis is also involved in the pathogenesis of HACE, which mainly leads to abnormal activation of microglia and destruction of tight junction of vascular endothelial cells through the excessive production of mitochondrial-related reactive oxygen species. Therefore, this review summarizes the role of REDOX homeostasis and the potential of the treatment of REDOX homeostasis in HACE, which is of great significance to expand the understanding of the pathogenesis of HACE. Moreover, it will also be helpful to further study the possible therapy of HACE related to the key link of REDOX homeostasis.

Hiccups and Slurring of Speech: Atypical Presentation of High-Altitude Cerebral Edema.

High-altitude cerebral edema (HACE) is one of the rare and severe form of high-altitude mountain sickness. Usually it presents as headache, altered mental status, ataxia in un-acclimatized person with rapid ascent to high altitude. Here we report a case of a 62-year-old male patient who had history of rapid ascent to high altitude and presented to the department of emergency after descent from high altitude with an atypical presentation as hiccups and slurring of speech. Magnetic resonance imaging (MRI) of brain showed white matter edema suggestive of HACE. The patient improved after treatment with supplemental oxygen, dexamethasone, and acetazolamide. He was discharged after three days of hospital stay with complete resolution of symptoms.

Hyperbaric oxygen preconditioning for prevention of acute high-altitude diseases: Fact or fiction?

Acute high-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), have been recognized as potentially lethal diseases for altitude climbers. Various preconditioning stimuli, including hyperbaric oxygen (HBO), have been proposed to prevent acute high-altitude diseases. Herein, we reviewed whether and how HBO preconditioning could affect high-altitude diseases and summarized the results of current trials. Evidence suggests that HBO preconditioning may be a safe and effective preventive method for acute high-altitude diseases. The proposed mechanisms of HBO preconditioning in preventing high-altitude diseases may involve: 1) protection of the blood-brain barrier and prevention of brain edema, 2) inhibition of the inflammatory responses, 3) induction of the hypoxia-inducible factor and its target genes, and 4) increase in antioxidant activity. However, the optimal protocol of HBO preconditioning needs further exploration. Translating the beneficial effects of HBO preconditioning into current practice requires the "conditioning strategies" approach. More large-scale and high-quality randomized controlled studies are needed in the future.

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Objective: To establish an animal model of high-altitude cerebral edema (HACE), to explore the altitude and oxygen partial pressure conditions that can lead to obvious clinical manifestations of HACE, and to lay the foundation for further research of the pathogenic mechanisms and intervention strategies of HACE. Methods: Male BALB/c mice of 8 weeks old were randomly assigned to Control and HACE groups. The Control group (n=10) was treated with normobaric and normoxic conditions, while the HACE groups were placed in hypobaric hypoxic (HH) chambers for the durations of 6 h, 12 h, 24 h, 48 h and 72 h, respectively, receiving treatments of simulated HH conditions at the altitudes of 4000 m (n=10 for each group receiving different durations of HH treatment), 5000 m (n=10 for each group receiving different durations of HH treatment), and 6000 m (n=10 for each group receiving different durations of HH treatment). HE staining was performed to observe the morphological changes of the brain tissue and the appropriate simulated altitude conditions were selected accordingly for the construction and evaluation of the best HACE model. The HACE model was evaluated in the following ways, the mouse brain was weighed and the cerebral edema was measured accordingly, Evans blue (EB) was injected to determine the permeability of the blood-brain barrier (BBB), and the cell apoptosis was determined by immunofluorescence staining. Results: There were no deaths in the groups treated with the HH conditions of the altitudes of 4000 m and 5000 m, while the mortality in the 6000 m altitude treatment groups was 12.2%. HE staining showed no significant changes in brain morphology or structure in the group receiving HH treatment for the altitude of 4000 m. A small amount of brain cell edema was observed in the groups receiving 48 h and 72 h of HH treatment for the altitude of 5000 m. The groups receiving HH treatment for the altitude of 6000 m demonstrated the most prominent modeling effect. HE staining showed increased volume and swelling of brain cells in all the 6000 m groups, especially in the 24 h, 48 h and 72 h treatment groups. In all the 6000 m groups, cell arrangement disorder, gap enlargement, and nuclear contraction were observed. Evaluation of the modeling effect demonstrated that, in the HACE mice model constructed with the HH conditions for the altitude of 6000 m, cerebral edema and EB permeability increased after 12 h HH treatment and there was no obvious apoptosis in the modeling groups receiving different durations of treatment. Conclusion: The HACE model can be established effectively by simulating conditions at the altitude of 6000 m (the atmospheric pressure being 47.19 kPa and the oxygen partial pressure being 9.73 kPa) with a HH chamber.

Severe Respiratory Failure Developing in the Course of High-Altitude Pulmonary Edema in an Alpinist with COVID-19 Pneumonia: A Case Report.

Pigon, Katarzyna, Ryszard Grzanka, Ewa Nowalany-Kozielska, and Andrzej Tomasik. Severe respiratory failure developing in the course of high-altitude pulmonary edema in an alpinist with COVID-19 pneumonia: a case report. High Alt Med Biol. 23:372-376, 2022.-The case of a 38-year-old Polish alpinist, evacuated from base camp (4,200 m) under Lenin's Peak due to severe high-altitude pulmonary edema (HAPE) and symptoms of acute mountain sickness/high-altitude cerebral edema (HACE), is presented. Starting the expedition, the man was asymptomatic and had a negative COVID-19 molecular test. After a few days of trekking, he developed typical HAPE and HACE. After evacuation to the hospital in Bishkek, a diagnosis of acute bronchopneumonia was made by computed tomography (CT) imaging. A COVID-19 test was not performed at that time. After returning to Poland, a complete noninvasive cardiac and pulmonary assessment disclosed no pathology. The initial chest CT reassessment was read as demonstrating the densities typical for COVID-19 pneumonia, and a SARS-CoV-2 antibody test corroborated the diagnosis. Pre-existing lung disease increases the risk of developing HAPE. In the era of the COVID-19 pandemic, people traveling at a high altitude and unaware of the infection are at particular risk.

Magnetic Resonance Imaging Evaluation of Suspected High-Altitude Cerebral Edema in Patients from High Altitude.

BACKGROUND: Trekkers in high altitude of Himalayas could lead to Acute Mountain Sickness and High Altitude Cerebral Edema. This study was conducted to evaluate magnetic resonance imaging findings among the clinically suspected High Altitude Cerebral Edema patients rescued from high altitudes in Nepal Himalayas. METHODS: 49 patients with clinically suspected High Altitude Cerebral Edema were retrospectively evaluated in this cross-sectional study who were sent for a brain magnetic resonance imaging. They were categorized in 3 groups according to the magnetic resonance imaging features in this study. RESULTS: There was a slight male preponderance. 6 patients (12.25%) had magnetic resonance imaging findings highly suggestive of High Altitude Cerebral Edema. 5 patients had T2 high signal intensity and restricted diffusion in the splenium of corpus callosum of which 3 had features of microhemorrhage. One patient with normal brain morphology and intensity in T1, T2, and FLAIR images showed innumerable variable-sized microhemorrhages in Susceptibility Weighted Imaging. 14 of patients showed various T2 and FLAIR white matter high signal intensity without restricted diffusion. And one patient had features of subacute lacunar infarcts. 28 patients (57.14 %) showed no abnormal signal changes in the magnetic resonance imaging scan. CONCLUSIONS: Typical magnetic resonance imaging features of cytotoxic edema in corpus callosum and microhemorrhage in the patients with High Altitude Cerebral Edema further support the findings in other similar studies. T2 white matter hyperintensities in deep, subcortical or periventricular location and lacunar infarcts could be seen in High Altitude Cerebral Edema. Normal magnetic resonance imaging of the brain is not infrequent.

Transcriptome of pituitary function changes in rat model of high altitude cerebral edema.

High altitude cerebral edema (HACE) is a serious subtype of acute mountain sickness (AMS). Studies have suggested that increased expression of corticotropin releasing hormone receptor 1 (CRFR1) in pituitary is related to the development of HACE, but no study has revealed the molecular landscape of pituitary function changes in this process. Rat model of HACE was established by simulating the high-altitude hypobaric hypoxia environment. Then RNA-sequencing was performed of rat pituitary gland (PG) in HACE and non-HACE groups. The function annotations, enrichment analysis, protein-protein interaction (PPI) network, chromosome location and drug repositioning of differentially expressed genes (DEGs) were explored based on the transcriptomic data. And we found pituitary secretion function was disordered in HACE, which was partly due to activated inflammation and oxidative stress. In addition, we identified potential biomarkers for early recognition of pituitary dysfunction and potential protective drugs for pituitary function in HACE.

Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema.

BACKGROUND: High-altitude cerebral edema (HACE) is a serious and potentially fatal brain injury that is caused by acute hypobaric hypoxia (HH) exposure. Vasogenic edema is the main pathological factor of this condition. Hypoxia-induced disruptions of tight junctions in the endothelium trigger blood‒brain barrier (BBB) damage and induce vasogenic edema. Nuclear respiratory factor 1 (NRF1) acts as a major regulator of hypoxia-induced endothelial cell injury, and caveolin-1 (CAV-1) is upregulated as its downstream gene in hypoxic endothelial cells. This study aimed to investigate whether CAV-1 is involved in HACE progression and the underlying mechanism. METHODS: C57BL/6 mice were exposed to HH (7600 m above sea level) for 24 h, and BBB injury was assessed by brain water content, Evans blue staining and FITC-dextran leakage. Immunofluorescence, transmission electron microscope, transendothelial electrical resistance (TEER), transcytosis assays, and western blotting were performed to confirm the role and underlying mechanism of CAV-1 in the disruption of tight junctions and BBB permeability. Mice or bEnd.3 cells were pretreated with MßCD, a specific blocker of CAV-1, and the effect of CAV-1 on claudin-5 internalization under hypoxic conditions was detected by immunofluorescence, western blotting, and TEER. The expression of NRF1 was knocked down, and the regulation of CAV-1 by NRF1 under hypoxic conditions was examined by qPCR, western blotting, and immunofluorescence. RESULTS: The BBB was severely damaged and was accompanied by a significant loss of vascular tight junction proteins in HACE mice. CAV-1 was significantly upregulated in endothelial cells, and claudin-5 explicitly colocalized with CAV-1. During the in vitro experiments, hypoxia increased cell permeability, CAV-1 expression, and claudin-5 internalization and downregulated tight junction proteins. Simultaneously, hypoxia induced the upregulation of CAV-1 by activating NRF1. Blocking CAV-1-mediated intracellular transport improved the integrity of TJs in hypoxic endothelial cells and effectively inhibited the increase in BBB permeability and brain water content in HH animals. CONCLUSIONS: Hypoxia upregulated CAV-1 transcription via the activation of NRF1 in endothelial cells, thus inducing the internalization and autophagic degradation of claudin-5. These effects lead to the destruction of the BBB and trigger HACE. Therefore, CAV-1 may be a potential therapeutic target for HACE. Video abstract.

Impact of Moderate Altitude on Lung Diseases and Risk of High Altitude Illnesses

ABSTRACT A large world population resides at moderate altitudes. In the Valley of Mexico (2240 m above sea level) and for patients with respiratory diseases implies more hypoxemia and clinical deterioration, unless supplementary oxygen is prescribed or patients move to sea level. A group of individuals residing at 2500 or more meters above sea level may develop acute or chronic mountain disease but those conditions may develop at moderate altitudes although less frequently and in predisposed individuals. In the valley of México, at 2200 m above sea level, re-entry pulmonary edema has been reported. The frequency of other altitude-related diseases at moderate altitude, described in skiing resorts, remains to be known in visitors to Mexico City and other cities at similar or higher altitudes. Residents of moderate altitudes inhale deeply the city's air with all pollutants and require more often supplementary oxygen.

(-)-Epicatechin gallate prevents inflammatory response in hypoxia-activated microglia and cerebral edema by inhibiting NF-κB signaling.

High-altitude cerebral edema (HACE), a potentially lethal disease, is associated with a time-dependent exposure to altitude-related hypobaric hypoxia (HH) and has reportedly been associated with microglia hyperactivation. Catechins are substances with good antioxidant properties, among which (-)-epigallocatechin gallate (EGCG) may play a neuroprotective role through the inhibition of microglia overactivation; however, the function of its analog- (-)-epicatechin gallate (ECG)-requires further elucidation. The aim of the present study was to investigate whether ECG prevented HACE by inhibiting HH-activated microglia. Primary microglia exposed to lipopolysaccharide (LPS)/ATP were co-treated with EGCG, ECG, and (-)-epigallocatechin, and ECG and EGCG exerted significant anti-inflammatory and neuroprotective effects. ECG inhibited the NF-κB pathway to prevent the activation of microglia induced by 1% O2. In addition, ECG ameliorated the increase in brain water content and aquaporin 4 expression induced by HH in mice. ECG also reduced the number of Iba1+ microglia in the brain, the release of proinflammatory factors, and the recruitment of microglia to blood vessels in HH-exposed mice. The outcomes of the present study revealed that ECG alleviated hypoxic hyperactivated microglia, reduced the neuroinflammation and blood-brain barrier permeability, and prevented HACE by inhibiting NF-κB signaling.

High-altitude illness: Menace in Himalayas of Nepal.

Nepal is a country of Himalayas including Mt Everest, the tallest mountain in the world, where a lot of people travel to high altitudes. Significant number of people develop high-altitude illness which includes acute mountain sickness (AMS), high altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE) leading even to death. Addressing this issue demands more efforts on both the preventive and treatment aspects to decrease the sufferings of people in this modern time of advanced healthcare and technology.

Impact of moderate altitude on lung diseases and risk of high altitude illnesses.

A large world population resides at moderate altitudes. In the Valley of Mexico (2240 m above sea level) and for patients with respiratory diseases implies more hypoxemia and clinical deterioration, unless supplementary oxygen is prescribed or patients move to sea level. A group of individuals residing at 2500 or more meters above sea level may develop acute or chronic mountain disease but those conditions may develop at moderate altitudes although less frequently and in predisposed individuals. In the valley of México, at 2200 m above sea level, re-entry pulmonary edema has been reported. The frequency of other altituderelated diseases at moderate altitude, described in skiing resorts, remains to be known in visitors to Mexico City and other cities at similar or higher altitudes. Residents of moderate altitudes inhale deeply the city's air with all pollutants and require more often supplementary oxygen.

Expert group syndrome at high altitude.

During a training session for the university diploma of Mountain medicine delivered by University Sorbonne Paris Nord for medical doctors, one of the participants developed signs of maladaptation to high altitude at 3 600 m, the severity of which was incorrectly interpreted. Information was sparingly given by the patient (an anesthetist) to several of his colleagues and no one was in charge to collect clinical data, take a history, and provide appropriate treatment. The combination of the absence of designation of a supervising doctor and the difficulty of communicating with the patient led to a lack of coordinated management and to an evolution of the symptoms towards severe acute mountain sickness. Fortunately, the very rapid management of the patient and a rapid helicopter evacuation, as soon as the symptoms worsened towards the onset of a suspected high altitude cerebral and/or pulmonary edema, allowed rapid resolution without sequelae. Environmental, medical, psychological, and managerial factors led to this Expert Group Syndrome.

Pathophysiology and Therapy of High-Altitude Sickness: Practical Approach in Emergency and Critical Care.

High altitude can be a hostile environment and a paradigm of how environmental factors can determine illness when human biological adaptability is exceeded. This paper aims to provide a comprehensive review of high-altitude sickness, including its epidemiology, pathophysiology, and treatments. The first section of our work defines high altitude and considers the mechanisms of adaptation to it and the associated risk factors for low adaptability. The second section discusses the main high-altitude diseases, highlighting how environmental factors can lead to the loss of homeostasis, compromising important vital functions. Early recognition of clinical symptoms is important for the establishment of the correct therapy. The third section focuses on high-altitude pulmonary edema, which is one of the main high-altitude diseases. With a deeper understanding of the pathogenesis of high-altitude diseases, as well as a reasoned approach to environmental or physical factors, we examine the main high-altitude diseases. Such an approach is critical for the effective treatment of patients in a hostile environment, or treatment in the emergency room after exposure to extreme physical or environmental factors.

Protective effect of 5,6,7,8-Tetrahydroxyflavone on high altitude cerebral edema in rats.

High altitude cerebral edema (HACE) is a potentially life-threatening disease encountered at high altitudes. However, effective methods for HACE prophylaxis are limited. Convincing evidence confirms that oxidative stress induced by hypobaric hypoxia (HH) is one of the main factors that account for the development of HACE. 5,6,7,8-Tetrahydroxyflavone (THF), a flavone with four consecutive OH groups in ring A, exhibited excellent antioxidant activity in vitro and could attenuate HH induced injury in vivo. The aim of this study was to investigate the protective effect of THF against HACE and its underlying mechanisms. THF administration significantly suppressed HH induced oxidative stress by reducing the formation of hydrogen peroxide and malondialdehyde, by increasing the levels of glutathione and superoxide dismutase in brain tissue. Simultaneously, THF administration inhibited inflammatory responses by decreasing the levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in serum and brain tissue. In addition, THF administration mitigated the energy metabolism disorder induced by HACE as evidenced by decreased levels of lactic acid, lactate dehydrogenase and pyruvate kinase as well as increased ATP levels and ATPase activities. Furthermore, THF administration decreased the expression of matrix metalloproteinase-9, aquaporin 4, hypoxia-inducible factor-1α and vascular endothelial growth factor, which attenuated blood-brain barrier (BBB) disruption and brain edema. Additionally, THF administration improved HACE induced cognitive dysfunction. These results show that THF is a promising agent in the prevention and treatment of HACE.

NRF1-mediated microglial activation triggers high-altitude cerebral edema.

High-altitude cerebral edema (HACE) is a potentially fatal encephalopathy associated with a time-dependent exposure to the hypobaric hypoxia of altitude. The formation of HACE is affected by both vasogenic and cytotoxic edema. The over-activated microglia potentiate the damage of blood-brain barrier (BBB) and exacerbate cytotoxic edema. In light with the activation of microglia in HACE, we aimed to investigate whether the over-activated microglia were the key turning point of acute mountain sickness to HACE. In in vivo experiments, by exposing mice to hypobaric hypoxia (7000 m above sea level) to induce HACE model, we found that microglia were activated and migrated to blood vessels. Microglia depletion by PLX5622 obviously relieved brain edema. In in vitro experiments, we found that hypoxia induced cultured microglial activation, leading to the destruction of endothelial tight junction and astrocyte swelling. Up-regulated nuclear respiratory factor 1 (NRF1) accelerated pro-inflammatory factors through transcriptional regulation on nuclear factor kappa B p65 (NF-κB p65) and mitochondrial transcription factor A (TFAM) in activated microglia under hypoxia. NRF1 also up-regulated phagocytosis by transcriptional regulation on caveolin-1 (CAV-1) and adaptor-related protein complex 2 subunit beta (AP2B1). The present study reveals a new mechanism in HACE: hypoxia over-activates microglia through up-regulation of NRF1, which both induces inflammatory response through transcriptionally activating NF-κB p65 and TFAM, and enhances phagocytic function through up-regulation of CAV-1 and AP2B1; hypoxia-activated microglia destroy the integrity of BBB and release pro-inflammatory factors that eventually induce HACE.

NB-3 expression in endothelial cells contributes to the maintenance of blood brain barrier integrity in a mouse high-altitude cerebral edema model.

NB-3, a member of the contactin/F3 subgroup in the immunoglobulin superfamily, plays an important role in neural development and injury recovery. The blood brain barrier (BBB) is typically involved in the pathophysiology of neural disorders, such as hypoxic-ischemic brain injury. Our previous research found that NB-3 protects against brain damage in a mouse stroke model. However, its role in high-altitude disorders caused by hypobaric hypoxia exposure remains unknown. In the present study, we found that NB-3 was expressed in brain microvascular endothelial cells (BMECs) and responded to hypoxia stimulation. Conditional knockout of NB-3 in endothelial cells increased BBB leakage and downregulated tight junction proteins in vivo. NB-3 deficiency promoted the downregulation of tight junction proteins under Lipopolysaccharide (LPS)/hypoxia stimulation. Conversely, overexpression or supplementation with NB-3 alleviated endothelial barrier injuries. Transcriptome sequencing showed that NB-3 regulated various cell attachment genomic changes, including the Notch signaling pathway. Blocking the Notch signaling pathway increased VEGF/VEGFR2 pathway activation induced by LPS/hypoxia. Collectively, we present evidence that NB-3 plays key roles in maintaining BBB integrity under high-altitude cerebral edema conditions.