Chronic high‐altitude exposure and intracerebral hemorrhage: A novel perspective from the vascular‐immune‐neuronal network

Abstract

Intracerebral hemorrhage (ICH) under chronic high‐altitude exposure exhibits distinct epidemiological characteristics: higher incidence, younger age at onset, more severe perihematomal edema, and worse clinical outcomes. However, the specific mechanisms underlying its pathogenesis and progression remain incompletely understood. In this review, we demonstrate that immigrant populations subjected to chronic high‐altitude exposure are at increased risk of ICH relative to indigenous populations (Tibetans, Andeans), primarily due to the lack of adaptive genetic variations such as endothelial PAS domain protein 1 and small ubiquitin‐like modifier‐specific peptidase 1. Additionally, high‐altitude polycythemia, high‐altitude hypertension, and hyperuricemia have been identified as critical risk factors for high‐altitude ICH. Further mechanistic exploration reveals that chronic high‐altitude exposure‐induced brain injury is structurally underpinned by vascular‐immune‐neuronal network dysfunction, which entails the interactive crosstalk of “vascular injury‐immune infiltration‐neurodegeneration” and thereby creates a unique pathological niche for high‐altitude ICH. At the molecular level, the core driving mechanism is the reciprocal activation of the hypoxia‐inducible factor pathway, oxidative stress, and neuroinflammation. This review represents a comprehensive synthesis of chronic high‐altitude exposure‐related brain injury and the subsequent exacerbation of ICH, providing a valuable reference for future research on high‐altitude encephalopathy.

Long‐term chronic high‐altitude hypobaric hypoxia increases susceptibility to ICH, particularly among migrant populations lacking EPAS1/SENP1 adaptive genetic variants relative to high‐altitude indigenous residents. Persistent hypoxia initiates blood–brain barrier (BBB) breakdown, aberrant glial and immune activation, and progressive neuronal injury; the reciprocal pathological crosstalk of these three pathological events, synergistically driven by concurrent HIF pathway activation, oxidative stress, and neuroinflammation, constructs a core pathogenic niche that exacerbates perihematomal edema, expands hematoma volume, and ultimately leads to unfavorable clinical prognosis following high‐altitude.

Highlights

• Long‐term exposure to high‐altitude hypoxic environments significantly increases the incidence and severity of intracerebral hemorrhage, and high‐altitude migrants exhibit more severe neurological deficits after hemorrhage due to the lack of high‐altitude adaptive genes.

• The worse clinical outcomes of intracerebral hemorrhage at high altitudes are primarily attributed to the specific pathological basis of brain injury induced by chronic high‐altitude exposure.

• Chronic high‐altitude exposure can exacerbate the pathological injury of intracerebral hemorrhage by disrupting the vascular‐immune‐neuronal regulatory network.

• The overactivation of hypoxia‐inducible factors, enhanced oxidative stress, and amplified neuroinflammation act synergistically to constitute the key molecular mechanisms underlying high‐altitude brain injury.

1. INTRODUCTION

Intracerebral hemorrhage (ICH) is a pressing global public health challenge, noted for its rapid onset, severe clinical presentation, and poor prognosis. ¹ ICH occurring in high‐altitude regions has increasingly attracted focus due to its unique pathophysiological and epidemiological features (Table 1). Medically, a high‐altitude is defined as an environment above 2500 m altitude, ¹⁶ , ¹⁷ characterized by hypoxia, hypobaria, and low temperatures ¹⁷ ; more than 80 million individuals worldwide inhabit areas at this elevation or higher. ¹⁶ , ¹⁸ ICH following chronic high‐altitude exposure diverges sharply from plain‐region ICH in epidemiology: it exhibits higher incidence, alongside elevated mortality and disability rates. ¹⁹ A meta‐analysis reported that the overall stroke incidence in high‐altitude areas is 0.5%, ² markedly exceeding the global stroke prevalence (0.14%) ³ ; critically, ICH constitutes a larger proportion of these strokes than in low‐altitude regions. In a Qinghai‐Tibet high‐altitude population cross‐sectional study (n = 10,056), stroke prevalence was 2.3% (95% CI: 2.0% to 2.6%), with 26.2% (95% CI: 25.3% to 27.0%) being high‐risk; both outcomes correlated positively with altitude (p < 0.01), supporting high‐altitude exposure as an independent stroke risk factor. ⁴ 2019 data from China's Hospital Quality Monitoring System ⁵ further highlighted this disparity: ICH accounts for 49.5% of stroke subtypes in Xizang's tertiary public hospitals, a figure far higher than the global ICH share of strokes (28.8%). ⁶ These striking epidemiological patterns underscore the need to elucidate the unique pathological mechanisms underlying high‐altitude‐associated ICH—particularly the role of vascular‐immune‐neuronal (VIN) network dysfunction, a focus of the present review.

Table 1.

Epidemiological characteristics of intracerebral hemorrhage (ICH) in chronic high‐altitude exposure versus plain regions.

Category	High‐altitude region	Plain region	References
Epidemiological Rates	‐ Stroke prevalence: 2.3% (Qinghai–Xizang plateau, n = 10,056), rising with altitude ‐ ICH proportion in stroke: 49.5% (tertiary hospitals in Xizang) ‐ Overall stroke incidence: 0.5%	‐ Global stroke prevalence: 0.14% ‐ Global ICH proportion in stroke: 28.8%	[2, 3, 4, 5, 6]
Population Characteristics	‐ Mean age: 50–60 years ‐ Male predominance: 64.0% ‐ Hypertension prevalence: 69.9%–83.6% ‐ Elevated hemoglobin: mean 163.7 g/L	‐ Mean age: >65 years; ‐ Hypertension prevalence: 60.5% ‐ Hemoglobin: mean 134.8 g/L	[5, 7, 8]
Clinical Phenotypes	‐ Larger hematoma volume: 25.4 ml ‐ Severe perihematomal edema ‐ Lower GCS score (worse neurological deficit) ‐ Higher rate of hematoma expansion ‐ Higher early cognitive impairment incidence	‐ Hematoma volume: 18.9 ml ‐ Mild neurological deficit ‐ Lower cognitive impairment risk	[9, 10, 11, 12]
Subgroup Differences	‐ Migrants versus natives: Migrants have younger onset age, higher hemoglobin, higher brainstem hemorrhage rate ‐ Tibetan versus Han: Tibetans have higher infratentorial/brainstem hemorrhage, BLA susceptibility, rebleeding, and cerebral infarction risk	‐ Lower brainstem/infratentorial hemorrhage rate ‐ Lower BLA incidence (3.2% vs. 19.6% in Tibetans)	[8, 13, 14]
Clinical Outcomes	‐ In‐hospital mortality: 4.9% ‐ DAMA/death rate: 20.5% ‐ 1‐year mortality: 30.5% ‐ Disability risk: 2.5× higher than plain ‐ Longer hospital stay	‐ Lower mortality and disability risk ‐ Shorter hospital stay	[5, 7, 8, 15]

Note: This table summarizes comparative epidemiological features of ICH between populations with chronic high‐altitude exposure and those in plain regions, covering five core dimensions: epidemiological rates, population characteristics, clinical phenotypes, subgroup‐specific variations, and clinical outcomes.

Abbreviations: BLA, blister‐like aneurysm; DAMA, discharge against medical advice; GCS, Glasgow Coma Scale.

In terms of clinical phenotype, high‐altitude ICH patients exhibit distinct demographic and clinical features: they are younger (mean age 50–60 years) with a 64.0% male predominance, whereas plain‐region ICH patients typically have a mean age >65 years. ⁵ , ⁷ Relative to plain‐region residents, high‐altitude residents present more severe initial symptoms, larger hematomas, and more extensive perihematomal edema, alongside poorer short‐term prognosis ⁹ —specifically, larger hematoma volumes (25.4 vs. 18.9 ml), more severe perihematomal edema, ¹⁰ and greater neurological deficits (lower Glasgow coma Scale score). ⁹ , ¹¹ High‐altitude intracerebral hemorrhage patients also have a higher propensity for hematoma expansion compared to those in plain regions. ¹¹ Outcome data reveal: 4.9% in‐hospital mortality for high‐altitude ICH, a 20.5% discharge against medical advice (death rate, 30.5% 1‐year mortality, 2.5‐fold higher disability risk than plain‐region ICH patients, and significantly longer hospital stays. ⁵ , ⁷ , ⁸ Additionally, early post‐stroke cognitive impairment is significantly more common in high‐altitude environments than in plain regions; it is more frequent in indigenous than migrant high‐altitude populations, and hemorrhagic stroke patients carry a higher risk of cognitive impairment than patients with ischemic stroke. ⁴ These pronounced clinical phenotype disparities between high‐altitude and plain‐region ICH highlight the need to dissect the unique VIN mechanisms driving the severity of high‐altitude‐associated ICH, a gap the present review aims to address.

Population subgroup analysis demonstrates that high‐altitude immigrant patients with ICH present with younger onset ages, higher hemoglobin levels, and a greater prevalence of brainstem hemorrhage relative to indigenous populations. ¹² In three West China Hospital cross‐sectional studies comparing plateau‐dwelling Tibetan and plain‐region Han patients with ICH, Tibetans exhibited elevated rates of hypertension (83.6% vs. 60.5%), hemoglobin concentrations (mean 163.7 g/L vs. 134.8 g/L), brainstem/infratentorial hemorrhage (11.5% vs. 5.1% for both), and higher risks of hematoma expansion‐associated in‐hospital complications (20.5% vs. 10.4%) and cerebral infarction (59.0% vs. 9.7%). ⁷ Among Tibetans, all three primary hemorrhagic neurovascular disease subtypes (aneurysmal subarachnoid hemorrhage, spontaneous ICH, arteriovenous malformation) showed significantly higher rebleeding and infarction rates (p < 0.05): notably, Tibetans had a higher incidence of blood blister‐like aneurysms (BLAs) in aneurysmal subarachnoid hemorrhage (19.6% vs. 3.2%) and more infratentorial brainstem hemorrhage in spontaneous ICH (10.8% vs. 5.1%). ⁸ Most Qinghai‐Tibet high‐altitude ICH cases are complicated by hypertension; Tibetan patients face higher follow‐up disability/death risks than Chengdu plain patients, ¹³ and BLAs are a hemorrhage subtype susceptible to Tibetans. ¹⁵ Hypertension (69.9% prevalence in high‐altitude ICH patients) is the key driver of Tibetan ICH, while hypoxia‐induced hemoglobin elevation and blood viscosity increase exacerbate cerebral hypoperfusion, ⁵ worsening post‐ICH secondary brain injury. These subgroup‐specific clinical and demographic disparities highlight that population‐specific adaptive differences (e.g., genetic or physiological) interact with high‐altitude hypoxia to shape ICH pathogenesis—underscoring the need to explore VIN mechanisms tailored to high‐altitude populations, the focus of this review.

To synthesize, long‐term high‐altitude exposure results in markedly higher ICH incidence and severity in both indigenous and migrant populations compared to plain‐region cohorts. ¹⁴ However, the unique risk factors and core pathogenic mechanisms of high‐altitude‐induced ICH are not fully clarified; its clinical phenotype of “elevated incidence and greater severity” is presumably tied to chronic hypobaric hypoxia‐mediated systemic brain tissue injury. This review will focus on five domains: the clinical characteristics of high‐altitude ICH, its risk factors, pathological underpinnings, core injury mechanisms, and management considerations for high‐altitude ICH. Critically, it will center on the regulatory role of hypobaric hypoxia in the VIN network ²⁰ —the core framework guiding this analysis of high‐altitude ICH. This review is a systematic, in‐depth integrative analysis dedicated to high‐altitude ICH, which will address the unmet research needs in this field.

To comprehensively identify studies relevant to the theme of this review, a systematic and extensive literature search was conducted. Given the paucity of research directly focusing on the association between chronic high‐altitude exposure and ICH, a two‐stage “broad‐first then targeted” search strategy was adopted to ensure comprehensive coverage of core mechanisms and relevant interdisciplinary research findings in this field. Electronic searches were performed in the PubMed, Embase, Web of Science Core Collection, and China National Knowledge Infrastructure databases, with a supplementary search conducted for relevant publications in the three flagship journals Cell, Science, and Nature. The search timeframe spanned from the inception of each database to January 31, 2026, and the search strategy was constructed by combining keywords related to seven core concepts: chronic high‐altitude exposure, chronic mountain sickness, hypobaric hypoxia, brain injury, stroke, hemorrhagic stroke, and intracerebral hemorrhage. No strict restrictions were imposed on disease subtypes or specific pathophysiological outcomes to maximize search sensitivity. After removing duplicate records using bibliographic management software and excluding articles from predatory journals, an initial pool of 4329 unique records was obtained. Two independent reviewers performed double‐blind preliminary screening based on titles and abstracts, prioritizing studies published in the past decade and excluding those unrelated to brain injury induced by high‐altitude exposure or chronic hypoxia. Subsequent full‐text evaluations were conducted, and a total of 219 high‐quality studies focusing on the clinical characteristics and pathogenesis of secondary ICH following chronic high‐altitude exposure were finally included. This two‐step screening approach balances the comprehensiveness and targeting of evidence, providing a solid empirical basis for the mechanistic framework proposed in this review while effectively avoiding the omission of key seminal studies in this relatively emerging research field.

2. HIGH‐ALTITUDE EXPOSURE: DUAL EFFECTS ON ADAPTATION AND AGING

Long‐term high‐altitude exposure imposes dual, opposing impacts on humans: accelerated aging and adaptive regulation. Notably, the higher ICH incidence and severity in long‐term high‐altitude residents are tightly linked to hypoxia‐mediated accelerated aging; while indigenous high‐altitude populations partially counter this via genetic/physiological adaptations, both groups remain vulnerable to chronic mountain sickness (CMS). In the Qinghai‐Tibet plateau, the prevalence of CMS is 1.05%, 3.75%, and 11.83% at altitudes of 2261–2980 m, 3128–3980 m, and 4000–5226 m, respectively. ²¹ Similarly, no CMS cases were observed at altitudes of 2350–3000 m in Himachal Pradesh, India, while the prevalence rose to 13.3% at 3000–4150 m. ²² In Bolivia, the incidence of CMS among male populations in La Paz (3600 m) has been reported to range from 6% to 8%. Thus, CMS is predominantly observed in individuals residing at altitudes above 3000 m for a prolonged period (≥3 months).

In a 13,439‐participant high‐altitude cohort study, Wu et al. ²³ have demonstrated that prolonged high‐altitude exposure accelerates biological aging and precipitates aging‐related pathologies—specifically, activating cascades tied to inflammation, ²⁴ tau hyperphosphorylation, cognitive decline, and neurodegeneration. This includes upregulating neuronal kinases (extracellular signal‐regulated kinase, glycogen synthase kinase 3 β, cyclin‐dependent kinase 5) that drive tau hyperphosphorylation, elevating pro‐inflammatory cytokines (interleukin‐1 β [IL], IL‐6, tumor necrosis factor [TNF]‐α) to form neurofibrillary tangles, culminating in neurodegeneration. ²⁵ Burtscher and Samaja ²⁶ , ²⁷ further showed that chronic hypoxia exacerbates age‐related molecular dysfunction: reduced oxidative adenosine triphosphate (ATP) synthesis, oxidative damage, immune impairment, and dysregulated inflammation (key drivers of neuroinflammation). Critically, Iacono et al. ²⁸ found that hypoxia‐independent hypobaria alone induces phosphorylated tau (pTau) accumulation, neuroinflammation, and myelin loss in large mammal brains—pathological hallmarks that align with high‐altitude ICH's neurovascular damage. Genomically, Zhou et al. ²⁹ linked hypoxia‐inducible factor (HIF) pathway gene (Egl‐9 Family Hypoxia Inducible Factor 1 [EGLN1]) variants to high‐altitude adaptation; their dysregulation amplifies hypoxia‐induced oxidative stress (an upstream trigger of neuroinflammation). MacInnis and Koehle ³⁰ identified hypoxia‐driven telomere shortening as a core aging marker in high‐altitude populations, which correlates with persistent inflammatory activation.

However, long‐term indigenous high‐altitude populations (e.g., Tibetans, Andeans) have mitigated the aging impacts of high‐altitude exposure through genetic and physiological adaptations ³¹ , ³² , ³³ , ³⁴ —whereas migrant populations exhibit more marked accelerated aging. For instance, Wu et al. ²³ demonstrated that high‐altitude migrants show greater PhenoAge (phenotypic age) acceleration (2.23 years), while the effect is muted in indigenous groups. Genomic studies have elucidated the molecular basis of this adaptation: Zhou et al. ³⁵ identified adaptive variations in the Small Ubiquitin‐like Modifier specific peptidase 1 (SENP1) and acidic nuclear phosphoprotein 32 family member D genes among indigenous Andean populations through whole‐genome sequencing. Among these, the adaptive gene SENP1 can stabilize HIF and GATA binding protein 1 (GATA‐1) transcription factors via desumoylation: on the one hand, it promotes erythropoiesis mediated by the erythropoietin–erythropoietin receptor E (po‐EpoR) system to adapt to high‐altitude hypoxia; on the other hand, it upregulates vascular endothelial growth factor (VEGF) expression to enhance angiogenesis while regulating inflammation and immune‐related pathways. ²⁹ , ³⁵ The alternatively spliced NFKB1 variants (AS‐NFKB1) enriched in Andean Aymara populations regulate the activity of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) pathway: under normal conditions, they promote the expression of inflammatory and HIF‐targeted genes to promote erythropoiesis and facilitate adaptation to high‐altitude hypoxia; under inflammatory stress, they inhibit NF‐κB nuclear translocation to avoid excessive inflammatory damage. Furthermore, they maintain the homeostasis of the VIN network through the interaction of “inflammation regulation‐hypoxic response‐erythropoiesis,” forming the unique high‐altitude adaptation mechanism of this population. ³⁶ , ³⁷ The adaptive endothelial PAS domain protein 1 (EPAS1) alleles enriched in Tibetan populations can disrupt the hypoxic response activity of tissue‐shared enhancers (e.g., EPAS1 hypoxia‐responsive enhancer 5), ³⁸ , ³⁹ downregulating hypoxia‐inducible factor‐2α (HIF‐2α) expression. ⁴⁰ On the one hand, they inhibit excessive erythropoiesis to reduce blood viscosity ³⁴ , ³⁹ ; on the other hand, they regulate vasoconstriction/vasodilation‐related genes (such as angiotensin‐converting enzyme and vascular endothelial growth factor C) and inflammatory pathways, maintaining VIN network homeostasis through the synergistic effect of “hypoxic response regulation‐vascular homeostasis maintenance‐immune‐inflammatory balance” and achieving adaptive protection against high‐altitude hypoxia. ⁴¹ , ⁴² , ⁴³ In addition, epigenetic modifications including DNA methylation (DNA methyltransferase 3α [DNMT3α] regulating HIF‐2α), histone modifications (TIP60‐mediated acetylation, SIRT1‐mediated deacetylation), and miRNA regulation (inhibiting HIF‐2α degradation) can precisely modulate the expression of hypoxia‐responsive genes, balance acute hypoxic adaptation and chronic damage, and serve as the key molecular mechanism for the human body to rapidly adapt to high‐altitude environments and reduce disease risk. ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ In terms of sex, emerging evidence suggests that females exhibit greater advantages in high‐altitude adaptation. ⁴⁹ , ⁵⁰ , ⁵¹

Importantly, high‐altitude exposure carries inherent, unavoidable risks: even the most adaptable populations do not fully escape CMS risk (it does not abate with increasing altitude). ⁵² , ⁵³ Long‐term high‐altitude exposure thus maintains a latent risk of CMS, which remains linked to persistent low‐grade inflammation—a precursor to high‐altitude ICH.

3. RISK FACTORS FOR INTRACEREBRAL HEMORRHAGE IN CHRONIC HIGH‐ALTITUDE EXPOSURE

3.1. Chronic mountain sickness

CMS is a maladaptive syndrome triggered by long‐term high‐altitude exposure, with severe hypoxemia as its central pathological trait. Typical clinical presentations include polycythemia, dyspnea, palpitations, sleep disturbances, cyanosis, venous dilatation, headache, tinnitus, and dizziness. ²¹ , ⁵⁴ CMS not only elevates stroke and migraine risk ⁵⁵ but also correlates with increased incidence and mortality in stroke patients. ⁵⁶ , ⁵⁷ Its neurological symptoms likely tie to endothelial and vascular dysfunction ¹⁶ : hypoxemia, polycythemia, and concurrent increases in hemoglobin concentration, blood viscosity, and shear stress converge to induce vascular endothelial dysfunction ⁵⁸ , ⁵⁹ —a process involving free radical‐mediated inflammatory activation (a core driver of neuroinflammation) and depletion of vascular nitric oxide (NO) bioavailability. ⁶⁰ This endothelial dysfunction can further cause neuronal injury, impaired cerebral blood flow regulation, blood‐brain barrier (BBB) disruption (a precursor to ICH), and microvascular damage, culminating in brain dysfunction. ⁶¹ , ⁶² The inaugural CMS longitudinal study confirmed that CMS incidence rises significantly with extended high‐altitude exposure. ⁶³ Critically, CMS is frequently complicated by conditions that collectively serve as key high‐altitude ICH risk factors via unique pathological pathways; high‐altitude polycythemia (HAPC), high‐altitude hypertension, and hyperuricemia are the most prominent, with their specific mechanistic links outlined below.

3.2. High altitude polycythemia (HAPC)

HAPC is the body's central compensatory adaptation to hypoxia: it enhances oxygen transport by expanding red blood cell counts, a hallmark of short‐term high‐altitude acclimatization. ⁶⁴ , ⁶⁵ However, when red blood cell overproliferation meets HAPC criteria (hemoglobin [Hb] ≥ 210 g/L in males, ≥190 g/L in females), this protective response transitions to pathological injury—emerging as a critical ICH risk factor. ⁶⁴ , ⁶⁵ Research confirms HAPC elevates the risk of pulmonary hypertension and stroke ⁶⁶ , ⁶⁷ , ⁶⁸ ; Its ICH‐driving mechanisms center on vascular‐immune dysregulation (aligned with the VIN network framework):

First, excessive red blood cells raise blood viscosity, disrupting microcirculation: this triggers symptoms (headache, fatigue, sleep disturbances) and slows cerebral blood flow, increasing thrombosis risk ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ ; clots then precipitate ICH via vascular occlusion and hemodynamic dysfunction. ⁷⁴ Second, HAPC upregulates pro‐inflammatory factors (IL‐1β, IL‐2, chemokine [C‐C motif] ligand 2 [CCL2])—key mediators of neuroinflammation. These factors amplify oxidative stress, damage vascular endothelium, and compromise vessel integrity, worsening tissue hypoxia to create a pro‐ICH pathological microenvironment. ⁷⁵ , ⁷⁶ Third, HAPC induces pulmonary hypertension and heart failure ⁷⁷ and synergizes with high‐altitude hypertension to exacerbate cerebral vascular damage. ⁷⁸ Wei et al. ⁷⁹ , ⁸⁰ demonstrated hemoglobin concentration modulates high‐altitude hypertension‐related ICH outcomes: it correlates linearly with neurological recovery. Below 180 g/L, elevation has minimal effect; above 180 g/L, it impairs function—likely by disrupting blood flow, inducing cerebral hypoxia, and worsening edema (a key contributor to post‐ICH neuroinflammation).

Critically, HAPC patients exhibit bidirectional coagulation dysregulation—a key component of vascular‐immune dysfunction in the VIN network: baseline hypercoagulability promotes thrombosis, while hypocoagulability during bleeding exacerbates ICH severity. ⁸¹ They also frequently have thrombocytopenia, ⁸² , ⁸³ but residual platelets are abnormally activated ⁸⁴ —this phenotype directly correlates with larger hematoma volumes in high‐altitude ICH, ¹¹ and explains why hemoglobin concentrations >180 g/L worsen ICH outcomes ⁷⁹ (likely via amplified vascular permeability and neuroinflammation). Though HAPC begins as an adaptive hypoxia response, chronic progression drives multisystem pathological injury. ⁸⁵ Even after long‐term high‐altitude exposure, HAPC patients maintain elevated sphingosine‐1‐phosphate (S1P) levels (a mediator of vascular endothelial dysfunction), ⁸⁶ sustaining the pro‐pathological microenvironment. Genetically, the rs6710946 variant in the Erb‐B2 receptor tyrosine kinase 4 gene (ERBB4; enriched in indigenous Tibetan populations relative to migrant Han populations) increases HAPC susceptibility ⁸⁷ —potentially by modulating inflammatory signaling within the VIN network.

3.3. High‐altitude hypertension

Long‐term high‐altitude exposure acts as a key environmental driver of hypertension ⁷⁷ , ⁸⁸ ; combined with hypertension (a globally established independent ICH risk factor ⁶ , ⁸⁹ , ⁹⁰ ), their synergy markedly elevates ICH risk in high‐altitude populations. Multiple cross‐sectional analyses demonstrate that hypertension prevalence is significantly higher in high‐altitude versus low‐altitude groups, ⁷¹ with a curvilinear relationship between altitude and prevalence. ⁹¹ , ⁹² Long‐term high‐altitude residence also correlates with increased all‐cause and cardiovascular mortality in hypertensive patients. ⁹³

Hypoxia is the central driver of high‐altitude hypertension: as a potent sympathetic nervous system activator, sustained exposure amplifies muscle sympathetic activity in migrant peripheral vessels, triggering vasoconstriction and tachycardia—ultimately raising blood pressure. ⁹⁴ In indigenous high‐altitude populations, hemoglobin concentration exhibits a threshold effect on hypertension risk: >176 g/L significantly increases risk. ⁹⁵ , ⁹⁶ Migrants (vs. indigenous Tibetans) have higher hypertension risk, ⁹⁶ , ⁹⁷ likely reflecting indigenous genetic adaptations.

Clinically, high‐altitude essential hypertension patients (vs. low‐altitude peers) have higher systolic/diastolic pressure, poorer blood pressure control, and greater risk of hyperuricemia (HUA) and metabolic dysfunction (p = 0.03). ⁹⁸ Unique pathological traits include right ventricular overload and left ventricular compensation; as altitude rises, systemic inflammatory responses (a core driver of neuroinflammation in the VIN network) progressively intensify, linking to declining micro/macrocirculation. ⁹⁹ This cascade exacerbates cerebral vascular damage, amplifying ICH risk.

3.4. Hyperuricemia (HUA)

Long‐term high‐altitude exposure provokes metabolic dysregulation (exemplified by HUA ¹⁰⁰ , ¹⁰¹ )—this is particularly marked in high‐altitude migrants, ¹⁰² and metabolic abnormalities are a key driver of CMS. ¹⁰³ In high‐altitude environments, HUA amplifies ICH risk through multiple mechanisms: on one hand, systemic hypoxia induced by HAPC bidirectionally elevates serum uric acid levels by promoting excessive uric acid production and reducing renal uric acid excretion; on the other hand, hypoxia also induces hypertension through hemodynamic changes, and triggers glomerular injury via increased red blood cell counts, forming a “hypoxia‐HUA‐hypertension” pathological cycle. ¹⁰⁴

Epidemiological data show that the overall prevalence of HUA in high‐altitude migrants reaches 40.8%; multivariate logistic regression analysis confirms that HUA is significantly associated with altitude exposure duration, altitude exposure pattern, and HAPC. ¹⁰⁵ Proteomic and metabolomic studies have revealed the molecular characteristics of HUA: HUA patients have significantly elevated levels of uric acid (UA), creatine kinase, and lactate dehydrogenase, accompanied by reduced platelet counts; differential protein functional enrichment analysis shows that immune signaling pathways are upregulated in patients, while hemostasis‐related protein expression is downregulated ¹⁰⁶ —this molecular alteration further exacerbates bleeding risk. From an etiological perspective, both Mendelian randomization studies and meta‐analyses have confirmed a direct causal relationship between HUA and ICH, ¹⁰⁷ and HUA is closely associated with adverse outcomes in acute stroke. ¹⁰⁸ Additionally, uric acid levels are also significantly associated with increased ICH risk in young and middle‐aged hypertensive patients in high‐altitude regions, ¹⁰⁹ further highlighting its key role in the pathogenesis of high‐altitude cerebrovascular diseases.

In summary, CMS and its complications are important risk factors and exacerbating factors for high‐altitude ICH; their impact on high‐altitude ICH is clear, but systematic research reports are still lacking. Of course, risk factors for high‐altitude ICH also include but are not limited to gut microbiota, ¹¹⁰ , ¹¹¹ dietary structure, lifestyle, and healthcare conditions, ¹⁹ which require comprehensive and in‐depth research. The diagnostic criteria for CMS require Hb ≥210 g/L in males and ≥190 g/L in females; however, numerous studies have shown that hemoglobin levels increase under long‐term chronic high‐altitude exposure, and any elevation above 180 g/L will significantly exacerbate ICH injury. Therefore, regardless of the presence of CMS, or even regardless of hemoglobin elevation, ICH under long‐term chronic high‐altitude exposure is significantly more severe than in non‐high‐altitude regions (Table 2).

Table 2.

Key risk factors for intracerebral hemorrhage (ICH) under chronic high‐altitude (HA) exposure.

Risk Factor	Definition/diagnostic criteria	Core pathogenic mechanisms	Clinical associations with ICH	References
CMS/HAPC	Maladaptive syndrome from long‐term HA exposure Diagnosed with HA polycythemia (male Hb ≥210 g/L; female Hb ≥190 g/L)	Hypoxia → endothelial/vascular dysfunction (inflammation, NO scavenging) → impaired neurogenesis, cerebral blood flow dysregulation, BBB disruption: 1. Elevated blood viscosity → microcirculation disorder/thrombosis 2. Increased pro‐inflammatory cytokines (IL‐1β, CCL2) → endothelial injury 3. Bidirectional coagulopathy (hypercoagulability → thrombosis; hypocoagulability → exacerbated bleeding) 4. Abnormal platelet activation	Increases stroke/ICH risk Correlates with higher ICH morbidity/mortality Increases ICH risk; Hb >180 g/L worsens ICH Neurodamage/hematoma expansion; Tibetan‐specific genetic susceptibility (ERBB4 rs6710946)	[54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87]
HA Hypertension	Hypertension induced by long‐term HA exposure	Hypoxia → sympathetic activation → vasoconstriction/tachycardia; Hb>176 g/L → elevated hypertension risk	Higher prevalence than plain regions; Poorer blood pressure control Comorbid with HUA; increases ICH risk	[77, 84, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99]
HUA	Metabolic disorder (hyperuricemia) induced by long‐term HA exposure	Hypoxia → increased uric acid production/decreased renal excretion; “Hypoxia‐HUA‐hypertension” cycle (glomerular injury) Upregulated immune pathways/downregulated hemostatic proteins	40.8% prevalence in HA migrants Direct causal link to ICH Exacerbates ICH risk in young/middle‐aged hypertensive patients	[100, 101, 102, 103, 104, 105, 106, 107, 108, 109]

Note: This table summarizes the definitions, core pathogenic mechanisms, and clinical associations with ICH of three key risk factors (CMS/HA polycythemia, HA hypertension, HA hyperuricemia) induced by long‐term HA exposure.

Abbreviations: BBB, blood‐brain barrier; CCL2, monocyte chemoattractant protein‐1; CMS, chronic mountain sickness; ERBB4, Erb‐B2 receptor tyrosine kinase 4; HAPC, high altitude polycythemia; Hb, hemoglobin; HUA, hyperuricemia; IL, interleukin; NO, nitric oxide.

4. PATHOLOGICAL BASIS OF INTRACEREBRAL HEMORRHAGE AFTER CHRONIC HIGH‐ALTITUDE EXPOSURE

4.1. Changes in brain structure and cognitive function under chronic high‐altitude exposure

Chronic high‐altitude exposure first impairs the central nervous system (CNS); the long‐term hypoxic microenvironment it induces is the core trigger for brain structural remodeling and functional abnormalities, as well as a key pathological premise for the development of CMS and related ICH. Existing studies have confirmed that patients with CMS exhibit significant differences in gray matter and white matter volumes across multiple brain regions, and spontaneous brain activity shows abnormal patterns ¹¹² ; this dual alteration of structure and function may be a key mechanism underlying the development and progression of CMS. ⁵⁵ At the cognitive function level, high‐altitude hypoxia exerts a significant damaging effect on overall cognitive ability ¹¹³ , ¹¹⁴ : long‐term memory and perceptual functions are most severely affected, followed by executive control, attention, and psychomotor skills, while working memory is relatively mildly impacted. Notably, this cognitive impairment is cumulative, with its core pathological basis lying in sustained increases in neuroglial cell activation, axonal injury, and oxidative stress levels induced by long‐term high‐altitude exposure, ¹¹⁵ ultimately leading to the disruption of neural circuit integrity and functional decline. Magnetic resonance imaging studies have revealed that long‐term high‐altitude exposure results in reduced gray matter density in multiple cognition‐related brain regions, including the bilateral insula, temporal lobe, and superior frontal gyrus, as well as decreased fractional anisotropy in key white matter fiber tracts such as the corpus callosum, which constitutes a critical pathological substrate for high‐altitude‐associated cognitive impairment. The hippocampus is a primary target of high‐altitude hypoxia. Studies have shown that long‐term high‐altitude exposure can induce multi‐dimensional pathological changes in the hippocampus ¹¹⁶ , ¹¹⁷ : including neuronal apoptosis and functional impairment, oxidative stress homeostasis imbalance, abnormal neurotransmitter and receptor expression, and dysregulation of neural cell energy metabolism. These changes directly weaken the hippocampus's learning‐memory function and neuroprotective effects, further exacerbating overall cognitive dysfunction. The mechanism of cognitive impairment induced by chronic high‐altitude exposure is related to multi‐level damage: the high sensitivity of the brain to hypoxia leads to extensive neuronal damage and gray matter volume atrophy in key brain regions such as the hippocampus; meanwhile, increased BBB permeability exacerbates pathological damage to the CNS; sustained induction of oxidative stress responses and neuroinflammation in the long‐term hypoxic environment disrupts the microenvironmental homeostasis of neural cells; mitochondrial dysfunction further exacerbates energy metabolism dysregulation, ultimately collectively destroying the structural stability and functional integrity of neural circuits, ¹¹⁴ laying a pathological foundation for the occurrence of ICH.

4.2. Pathological basis of ICH after chronic high‐altitude exposure: An integrated perspective based on the VIN network

The hypobaric hypoxic environment induced by chronic high‐altitude exposure does not damage a single target in isolation; instead, it induces systematic remodeling and functional disruption of the vascular system, immune network, and neurons, forming a “vascular injury‐immune activation‐neuronal degeneration” pathological cascade reaction, which ultimately provides the core pathological basis for the occurrence of ICH (Figure 1). Below, we systematically elaborate on these from three dimensions (vascular, immune, and neuronal) and their interactions.

Figure 1.

Pathological network of vascular‐immune‐neuronal crosstalk underlying intracerebral hemorrhage (ICH) in chronic high‐altitude exposure. This diagram illustrates the integrated pathological cascade induced by chronic hypobaric hypoxia (chronic high‐altitude exposure): Initiating trigger: Chronic hypobaric hypoxia drives vascular system injury (Step 1), which serves as the structural basis for ICH—centered on blood‐brain barrier (BBB) disruption, with key mechanisms involving dysfunction of endothelial cells (tight junction downregulation, metabolic reprogramming), pericytes (HIF/RGS5‐mediated impairment), and astrocytes (inflammatory cytokine release, AQP4‐induced edema, Bach1‐mediated ferroptosis). Mediator bridge: BBB disruption enables peripheral‐central immune crosstalk, triggering immune network activation (Step 2)—characterized by peripheral immune dysregulation (monocyte/T‐cell infiltration via disrupted BBB) and central microglial M1 polarization (CX3CL1/CX3CR1 axis), with pro‐inflammatory cytokine (IL‐1β/TNF‐α) and mtROS release. Final pathological target: Immune signals directly induce neuronal injury (Step 3), manifested as mitochondrial dysfunction (12/15‐LOX‐mediated apoptosis), reduced neuronal excitability, impaired neurogenesis, and synaptic loss. The crosstalk (marked by arrows) between the three components forms a vicious cycle: BBB disruption facilitates immune infiltration (which further damages the BBB), while immune activation and vascular impairment synergistically drive neurodegeneration. This cascade ultimately increases ICH susceptibility and worsens clinical outcomes (larger hematoma, severe edema, neurofunctional deficit, high mortality). AQP4, aquaporin 4; BDNF, brain‐derived neurotrophic factor; CX3CL1, C‐X3‐C motif chemokine ligand 1; CX3CR1, C‐X3‐C motif chemokine receptor 1; DG, dentate gyrus; HIF, hypoxia‐inducible factor; IL‐1β, interleukin‐1β;12/15‐LOX: 12/15‐lipoxygenase; mtROS, mitochondrial reactive oxygen species; pCREB, phosphorylated cyclic adenosine monophosphate response element‐binding protein; PKM2, pyruvate kinase M2; RGS5, regulator of G‐protein signaling 5; TNF‐α, tumor necrosis factor‐α; ZO‐1, zonula occludens‐1.

4.2.1. Vascular system: Structural damage of ICH

The vascular system (especially the BBB) is the primary target of chronic high‐altitude hypoxia; its injury centers on BBB disruption, involving coordinated functional dysregulation of cerebral microvascular endothelial cells, pericytes, and astrocytes. The specific mechanisms are as follows:

High‐altitude hypobaric hypoxia is the core environmental stressor regulating BBB function, primarily inducing dual changes: loss of structural integrity and abnormal physiological function ¹¹⁸ , ¹¹⁹ and this process is dynamically regulated by cerebral microvascular endothelial cells, astrocytes, and pericytes. Hypoxia directly leads to functional dysregulation of these three cell types, causing downregulation of tight junction proteins (e.g., zonula occludens‐1 [ZO‐1], claudin‐5) or disordered spatial distribution, which ultimately significantly increases BBB permeability. Notably, the damage caused by high‐altitude hypoxia is extensive: in addition to the BBB, the integrity of the blood‐cerebrospinal fluid barrier and cerebrospinal fluid‐brain barrier is also disrupted, ¹²⁰ forming a pathological state of multi‐barrier leakage, which creates conditions for subsequent immune cell infiltration and nerve injury.

Cerebral microvascular endothelial cells: Key effector cells of BBB disruption. Endothelial cell dysfunction is the core link in BBB disruption; its functional decline is the result of the synergistic action of multiple hypoxia‐mediated mechanisms, including changes in blood flow shear stress, ¹²¹ enhanced oxidative stress, overactivation of sympathetic nerve activity, and abnormal increases in red blood cell concentration and quantity. Clinical evidence shows that healthy Tibetan and Andean highland residents can maintain normal endothelial function in high‐altitude environments, but Andean highland residents with CMS exhibit significant endothelial dysfunction, ¹²² suggesting that endothelial function is closely related to the pathological progression of CMS.

At the molecular mechanism level, integrated transcriptomic and targeted metabolomic analyses confirm that hypoxia induces vascular endothelial dysfunction through energy metabolism reprogramming ¹²³ : specifically, the metabolic mode of endothelial cells shifts from oxidative phosphorylation to glycolysis, leading to massive lactate accumulation; lactate overload can trigger lactylation modification of pyruvate kinase M2 (PKM2), stabilize the PKM2 protein by inhibiting the ubiquitination pathway, forming a positive feedback amplification loop, and ultimately exacerbate mitochondrial function collapse and endothelial dysfunction. Additionally, chronic hypoxia can also reduce endothelial‐dependent dilation by enhancing α‐adrenergic signaling. ¹²⁴ Moreover, vascular extravasation is not a side effect of angiogenesis‐related endothelial proliferation, but a direct pathological response to hypoxia‐mediated vascular dysfunction. ¹²⁵ Hypoxia can also inhibit the cell cycle progression and proliferation ability of cerebral microvascular endothelial cells through the miR‐212‐3p/MCM2 signaling axis, further exacerbating endothelial injury ¹²⁶ ; non‐coding RNAs may play a key regulatory role in modulating oxidative stress responses and hypoxic adaptability of endothelial cells. ¹²⁷

Multiple studies have validated the above pathological processes: Zhang et al. ¹²⁸ found that hypoxia can trigger Ca²⁺ influx in endothelial cells and other damaged cells, leading to decreased ATP levels and increased nitric oxide (NO) release, which in turn induces dysfunction of oxidative phosphorylation, glycolysis, and the tricarboxylic acid cycle, ultimately resulting in rearrangement of tight junction‐related proteins and increased BBB permeability; Berndt et al. ¹²⁹ confirmed that the increase in BBB permeability under hypoxic conditions is directly related to the downregulation of claudin‐5 and occludin expression in endothelial cells; Park et al. ¹³⁰ further pointed out that hypoxia can alter BBB permeability by regulating the phosphorylation status and subcellular redistribution of tight junction‐related proteins and nutrient receptors.

Pericytes: Hub of BBB stability and inflammatory response. Pericytes are localized at a critical position in the neurovascular unit, possessing multiple functions: maintaining BBB integrity, participating in angiogenesis, and secreting various bioactive molecules. Studies have found that, under in vitro hypoxic conditions, human brain‐derived pericytes exhibit a microglial cell phenotype and upregulate mRNAs specific to activated microglia. ¹³¹ The cellular and molecular responses of pericytes to hypoxia are mostly regulated by HIF; however, G protein signaling regulator 5 (RGS5), as a hypoxia‐sensing protein independent of HIF, plays a unique role in the hypoxic response of pericytes: under chronic hypoxic conditions, RGS5 expression is upregulated in pericytes, leading to abnormal cell migration, impaired BBB integrity, accompanied by neurovascular dilation and demyelination changes. ¹³² , ¹³³ Additionally, the surface of pericytes is rich in various inflammatory mediator receptors, which can respond to inflammatory signals such as monocyte chemoattractant protein‐1 and TNF‐α; they amplify inflammatory responses by secreting CCL2, nitric oxide, and multiple cytokines, making them the most sensitive cell type in the BBB to peripheral inflammation. ¹³⁴ Their functional abnormalities can further exacerbate inflammatory damage to central blood vessels.

Astrocytes: Dual regulators of BBB function and neuroinflammation. Astrocytes are core cells for maintaining BBB function and regulating central inflammation, exerting both adaptive and pathological effects in high‐altitude hypoxic environments. As the key effector cells for high‐altitude adaptation, astrocyte activation may participate in adaptive remodeling after chronic high‐altitude exposure ¹³⁵ ; however, long‐term high‐altitude exposure can downregulate Kir channels in astrocytes, thereby reducing potassium ion uptake capacity—this is one of the main molecular mechanisms underlying neurological symptoms in patients with CMS. ¹³⁶ In well‐adapted high‐altitude residents, astrocytes in the brain have lower sensitivity to intracellular pH for acid extrusion, a trait that prevents excessive activation of the sodium‐hydrogen exchanger during hypoxia‐induced intracellular acidosis, enhancing the body's tolerance to high‐altitude hypoxia. ¹³⁷ During acute hypoxia, BPGM expression is significantly upregulated in astrocytes, adapting to the hypoxic environment by enhancing glycolytic capacity ¹³⁸ , ¹³⁹ ; Its monocarboxylate transporter‐dependent mechanism also participates in the adaptive regulation of exercise‐induced fatigue. ¹⁴⁰ A stroke study identified benefits of hypoxia inducible factor 1α (HIF‐1α): it can reduce ischemic brain injury by regulating inflammatory responses and glial cell activity. ¹⁴¹

In maladaptive states, abnormal activation of astrocytes is a core pathological manifestation: during acute hypoxia or recurrent acute hypoxia on a chronic hypoxia basis, aquaporin 4 (AQP4) expression increases in astrocytes, triggering cerebral edema ¹⁴² , ¹⁴³ ; Chronic high‐altitude exposure can trigger pro‐inflammatory activation of microglia, leading to lipid droplet accumulation and IL‐1β release, which in turn drives lipid droplet accumulation and neuroinflammation in astrocytes, exacerbating cognitive impairment ¹⁴⁴ ; long‐term hypoxia can also induce activation of astrocytes and microglia, reduced expression of oligodendrocytes, and these glial cell changes have temporal and regional specificity (the hippocampal CA1 region is most sensitive), inducing neuroinflammation and intercellular interactions to drive neurodegeneration. ¹⁴⁵ Additionally, high‐altitude hypoxia can significantly enhance astrocyte ferroptosis by upregulating Bach1 expression, ¹⁴⁶ worsening high‐altitude traumatic brain injury ¹⁴⁷ ; a significant reduction in astrocyte generation is a characteristic manifestation of neurodevelopmental disorders induced by long‐term high‐altitude chronic hypoxia. ¹⁴⁸ In pathological states, astrocytes can secrete inflammatory factors such as CCL2 and CCL12, ¹⁴⁹ recruiting leukocytes to infiltrate the BBB region, which in turn increases phospho‐tyrosine activity and disrupts tight junction‐related protein connections, ultimately increasing BBB permeability.

4.2.2. Immune network activation: The mediating bridge between vascular‐neuronal injury

Chronic high‐altitude exposure can induce abnormal activation and crosstalk of peripheral and central immune networks; through amplification of inflammatory signals, it exacerbates vascular injury and neuronal degeneration, serving as a key mediator linking vascular and neuronal damage. The specific mechanisms are as follows:

4.2.2.1. Peripheral immune dysregulation and central infiltration

Long‐term chronic high‐altitude exposure can induce bidirectional crosstalk between peripheral and central immune cell activation, ¹⁵⁰ , ¹⁵¹ triggering systemic and persistent immune cell dysfunction. ¹⁵² Activation of inflammatory responses and impairment of immune effector functions, observed during extremely high‐altitude mountaineering, ¹⁵³ represent early immune adaptive changes in the human body's response to hypoxic environments; however, after long‐term high‐altitude exposure, immune dysfunction is mainly characterized by sensitization of inflammatory pathways, particularly abnormal activation of chemokine signaling. ¹⁵⁴ High‐altitude hypoxic exposure can directly alter the composition of peripheral immune cell populations, ¹⁵⁵ and this change is closely associated with the onset of acute mountain sickness.

From the perspective of pathological transmission, the peripheral immune system influences the brain's VIN network through multiple pathways ¹⁵⁶ : hypoxia‐mediated BBB disruption provides a structural basis for peripheral immune cell infiltration; peripheral immune cells (e.g., monocytes, T cells) can enter the brain via the BBB, meninges, and choroid plexus, interacting with central immune cells (microglia, border‐associated macrophages [BAMs]) and releasing pro‐inflammatory factors such as IL‐1β and TNF‐α, further exacerbating neuroinflammation. Meanwhile, immune cell infiltration can disrupt the integrity of vascular tight junctions, induce vascular leakage, and directly interfere with synaptic function and neurogenesis, ultimately worsening cognitive impairment. This pathological process is regulated by the HIF‐1α pathway, and the synergistic effect of peripheral and central immune cells determines the severity of injury. ¹⁵⁰ Notably, on the basis of pre‐existing BBB disruption, the crosstalk between peripheral and central immune systems is further enhanced when ICH occurs in high‐altitude environments, ¹⁵⁷ becoming a key driver of exacerbated edema and worsening neurological dysfunction after ICH. Studies have found that patients with systemic inflammatory response syndrome (SIRS) experience more severe ICH, characterized by larger hematoma volumes, higher incidence of intraventricular hemorrhage, and poorer neurological status on admission. ¹⁵⁸

4.2.2.2. Microglial activation: Core effector of central immune injury

Microglia coordinate neuron‐glial cell interactions and regulate neuronal activity by pruning astrocytes. ¹⁵⁹ The environmental plasticity of microglia ¹⁶⁰ makes their interaction with the neurovascular system a key link in maladaptation to high‐altitude hypobaric hypoxic environments. Under long‐term high‐altitude exposure, hypobaric hypoxia can directly activate microglia, which regulates brain function via the vascular‐immune‐neuronal network; its pathological effects manifest in three dimensions: specifically, in the immune dimension, they release cytokines such as IL‐15 and IL‐33 to remodel the brain's inflammatory microenvironment; in the vascular dimension, abnormal crosstalk with cerebral blood vessels further increases BBB permeability, while microglia's attenuated chemotactic response to vascular injury impairs vascular repair; in the neuronal dimension, they inhibit hippocampal long‐term potentiation, impair synaptic plasticity, and their region‐specific maladaptation further disrupts neuronal homeostasis. ¹⁶¹ Furthermore, mitochondrial reactive oxygen species (mtROS) can exacerbate microglia activation‐mediated neurotoxic damage to dendritic spine plasticity, ¹⁶² forming an “oxidative stress‐microglial activation‐neuronal injury” vicious cycle.

At the molecular mechanism level, high‐altitude exposure can mediate microglial polarization toward the M1 phenotype via the chemokine (C‐X3‐C motif) ligand 1 (CX3CL1)/CX3C chemokine receptor 1 (CX3CR1) signaling pathway and upregulate their phagocytic function—leading to excessive phagocytosis of synapses in the hippocampal CA1 region, which induces synaptic loss and forgetting behavior. ¹⁶³ These pro‐inflammatory microglia play an important role in secondary injury after ICH. ¹⁶⁴ Microglia also participate in the pathological progression of acute high‐altitude cerebral edema: studies confirm that redox homeostasis imbalance induced by high‐altitude hypoxia mainly occurs via excessive production of mitochondrial‐related ROS, which induces abnormal microglial activation (upregulating nuclear respiratory factor 1 [NRF1] ¹⁶⁵ ) and disruption of vascular endothelial cell tight junctions, thereby exacerbating acute high‐altitude cerebral edema, ¹⁶⁶ and this pathological process may exacerbate vascular leakage and brain tissue injury in high‐altitude ICH through similar mechanisms. ¹⁶⁴

4.2.3. Neuronal injury: The final target of pathological cascades

As the core functional unit of the vascular‐immune‐neuronal network, neurons are the final target of chronic high‐altitude hypoxia‐induced pathological cascade reactions; their injury mainly manifests as mitochondrial dysfunction, excitability abnormalities, neurogenesis inhibition, and inflammation‐mediated neurodegeneration. The specific mechanisms are as follows:

High‐altitude hypoxia can directly promote neuronal mitochondrial dysfunction, ultimately leading to neuronal apoptosis ¹⁶⁷ ; Another study confirmed that during hypobaric hypoxia, 12/15‐lipoxygenase can disrupt mitochondrial integrity, causing cytochrome c to be released into the cytoplasm and inducing neuronal death via the intrinsic pathway. ¹⁶⁸ Long‐term chronic high‐altitude exposure also leads to significant changes in neuronal excitability: the neuronal excitability of patients with CMS is much lower than that of non‐CMS patients, and this difference stems from a significant reduction in sodium channel current density, ¹⁶⁹ providing a cellular basis for CMS‐related neurological symptoms.

At the behavioral and neurogenesis levels, chronic hypobaric hypoxia can induce social recognition impairment and increased anxiety‐like behavior in rats, while inhibiting adult neurogenesis in the hippocampal dentate gyrus (DG) ¹⁷⁰ ; specifically, this is characterized by a reduction in the number of neural progenitor cells, immature neurons, and surviving neurons, as well as downregulation of brain‐derived neurotrophic factor (BDNF), serotonin, and phosphorylated cAMP response element‐binding protein (pCREB) levels. The core mechanism lies in the fact that chronic hypobaric hypoxia activates microglia and astrocytes, induces NOD‐Like Receptor Pyrin Domain‐Containing Protein 3 (NLRP3) inflammasome activation via the COX‐1/EP1R pathway, promotes the release of pro‐inflammatory factors such as IL‐1β, TNF‐α, and IL‐6, and disrupts the homeostasis of the vascular‐immune‐neuronal network. ¹⁷⁰ Additionally, the core effects of chronic high‐altitude hypobaric hypoxia on rat hippocampal neurons also include the sensitivity of neurons to hypoxic stress is significantly increased, ¹⁷¹ suggesting that changes in mitochondrial dynamics play a key role in the increased stress susceptibility of neurons in patients with CMS.

In summary, the effects of long‐term high‐altitude exposure on the brain do not exist in isolation; instead, it is a systematic pathological process with vascular system injury as the structural basis, immune network activation as the mediating bridge, and neuronal injury as the final result. The three interact and interfere with each other through a “vascular injury‐immune infiltration‐neurodegeneration” vicious cycle, ultimately reducing cerebrovascular stability and neuronal tolerance, and becoming the core pathological basis for the occurrence and poor prognosis of high‐altitude ICH. ¹⁷² Chronic high‐altitude exposure induces long‐term sensitization of the intracranial immune system via persistent hypoxia, priming the HIF‐NF‐κB pathway and pre‐activating microglia/astrocytes. Following ICH, the sensitized immune network rapidly triggers an excessive inflammatory response, which exacerbates BBB disruption, amplifies neuroinflammation, induces multiple types of neuronal cell death, and impairs tissue repair processes. This cascade ultimately results in more severe cerebral edema and pronounced neurological deficits, serving as the core driver of secondary brain injury after high‐altitude ICH (Figure 2). ¹⁷³ , ¹⁷⁴

Figure 2.

Comparative pathological landscape of brain vascular‐immune‐neuronal networks: Plain versus long‐term high‐altitude exposure. This dual‐panel diagram contrasts the brain microenvironment under physiological (plain region) and pathological (long‐term high‐altitude exposure) conditions: Left panel (Brain in plain): Represents the homeostatic state in the absence of hypobaric hypoxia. Cerebral vascular endothelium maintains stability; immune cells (e.g., neutrophils) are confined to blood vessels; astrocytes, neurons, and other brain parenchymal cells function normally, with no abnormal activation or tissue damage. Right panel (Long‐term high‐altitude‐exposed brain): Illustrates the pathological remodeling induced by chronic hypobaric hypoxia: 1). Vascular system injury: Endothelial activation (accompanied by cytokine release: interleukin‐6 [IL‐6], interleukin‐1β [IL‐1β], tumor necrosis factor‐α [TNF‐α], C‐C motif chemokine ligand 2 [CCL2]) disrupts the blood‐brain barrier (BBB); increased blood viscosity promotes thrombus formation. 2). Immune network activation: BBB disruption allows neutrophil infiltration into the brain parenchyma; pericytes, astrocytes, and microglia (polarized to pro‐inflammatory M1 phenotype) are activated, synergistically amplifying the inflammatory microenvironment; boundary‐associated macrophages (BAMs) also participate in pro‐inflammatory responses. 3). Neuronal injury: Inflammatory factors and immune cell‐derived signals induce neurotoxicity, ultimately leading to neuronal apoptosis. This contrast highlights that chronic high‐altitude exposure drives a vicious cycle of vascular damage‐immune activation‐neuronal degeneration, which is the core pathological basis for increased intracerebral hemorrhage susceptibility in high‐altitude populations.

5. CORE MOLECULAR MECHANISMS OF CENTRAL NERVOUS SYSTEM PATHOLOGICAL INJURY AFTER CHRONIC HIGH‐ALTITUDE EXPOSURE: INTERACTIVE DRIVING OF HIF‐1, OXIDATIVE STRESS, AND NEUROINFLAMMATION

The hypobaric hypoxic environment induced by chronic high‐altitude exposure activates three core pathways—hypoxia‐inducible factors (HIFs), oxidative stress, and neuroinflammation—forming a pathological network characterized by “mutual activation and cascade amplification.” This network collectively mediates CNS injury, serving as the core pathogenic mechanism of high‐altitude ICH and related neurological dysfunction. Below, we systematically elaborate on the interactive relationships and respective pathological effects of these three pathways:

Acute, intermittent, and chronic hypobaric hypoxic exposure can all induce oxidative stress, causing pathological changes in cellular components (e.g., lipids, proteins, DNA) and downstream molecular pathways. ¹⁷⁵ Studies on high‐altitude populations confirm that in patients with CMS, levels of oxidative stress markers (e.g., ascorbate free radicals) are significantly elevated, while levels of antioxidant biomarkers (e.g., ascorbate) are reduced; healthy high‐altitude residents exhibit moderate, persistent elevation of oxidative‐nitrosative stress (OXINOS), but this level does not impair vascular function—representing an essential difference from the equivalent stress observed in low‐altitude residents during acute hypoxia. ¹⁷⁶ Notably, systemic OXINOS elevation in patients with CMS is closely associated with reduced cerebral perfusion, decreased vascular reactivity in hypercapnia, cognitive impairment, and depressive symptoms. ⁵⁶

Mechanistically, ROS generated under oxidative stress (e.g., superoxide anions) inhibit prolyl hydroxylase domain enzyme activity, reduce HIF‐1α hydroxylation, prevent its degradation by the von Hippel‐Lindau (VHL) complex, promote HIF‐1α stabilization and nuclear translocation, and enhance HIF‐1α transcriptional activity. Under sustained hypoxia from long‐term chronic high‐altitude exposure, excessive HIF‐1 activation induces factors such as VEGF and BCL‐2/adenovirus E1B 19‐kDa interacting protein 3 (BNIP3), exacerbating vascular leakage and cell apoptosis; this indirectly amplifies oxidative stress‐induced tissue damage, leading to neuronal apoptosis, astrocyte activation, further accelerating BBB disruption, and worsening neuroinflammation.

5.1. Dual roles and isoform‐specific regulation of the HIF pathway

As oxygen‐sensitive transcriptional regulators, HIFs serve as the core “switch” for the body's hypoxic response ⁵³ , ¹⁷⁷ ; their family members (mainly HIF‐1α and HIF‐2α) exhibit isoform‐specific functional division and synergy during chronic high‐altitude exposure, with a functional transition from “adaptive protection” to “pathological injury.”

In angiogenesis and hypoxic adaptation: HIF‐1α is rapidly stabilized during acute hypoxia, driving the shift of cellular metabolism from oxidative phosphorylation to glycolysis, and initiating angiogenesis by activating endothelial cell and extracellular matrix remodeling; HIF‐2α, by maintaining the expression of genes related to vascular remodeling and maturation, regulates the adaptive response of cells to chronic hypoxia. ¹⁴ , ¹⁷⁸ , ¹⁷⁹ In long‐term chronic high‐altitude brain injury (regardless of CMS comorbidity), HIF‐2α dominates the regulation of vascular remodeling and erythropoiesis ¹⁷⁸ , ¹⁸⁰ , ¹⁸¹ ; while during high‐altitude ICH, secondary injury is dominated by HIF‐1α, which mainly mediates BBB disruption and cerebral edema formation. ¹⁵⁹ , ¹⁶²

In high‐altitude environments, HIF‐1α and HIF‐2α exhibit specific interactions: pre‐activation of HIF‐2α induced by chronic hypoxia can regulate HIF‐1α stability by promoting EGLN1 expression; they share key target genes (e.g., VEGF), forming a pathway overlap effect ¹⁷⁸ , ¹⁸¹ ; Meanwhile, by exacerbating inflammatory responses and constructing a hyperviscous blood microenvironment, they synergistically worsen CNS injury. ¹⁸⁰ This “chronic HIF‐2α pre‐activation‐acute HIF‐1α synergistic injury during ICH” model is unique to high‐altitude regions—unlike plain ICH, where there is no HIF‐2α pre‐activation process, and pathological injury is mediated solely by HIF‐1α. ¹⁸²

HIF‐1 is both a key marker of chronic high‐altitude adaptation and the core cause of CNS injury induced by long‐term hypoxia. ⁵³ , ¹⁷⁷ Sustained/excessive hypoxia can drive HIF‐1 from adaptive protection to pathological injury ¹⁸¹ ; its core pathological pathways involve synergistic injury of three units (immune, vascular, neuronal): Immune unit: Crosstalk with the NF‐κB pathway to activate microglia, induce the release of pro‐inflammatory factors (e.g., IL‐6, TNF‐α), and exacerbate neuroinflammation; meanwhile, promote neutrophil survival and macrophage activation, amplifying systemic inflammatory injury; Vascular unit: Over‐upregulate VEGF expression, disrupt the integrity of BBB tight junction proteins, increase vascular permeability, and induce cerebral edema; induce intraplaque angiogenesis, exacerbating cerebrovascular instability; Neuronal unit: Activate pro‐apoptotic genes (e.g., BNIP3, Noxa), trigger mitochondria‐mediated neuronal apoptosis; disrupt cellular calcium homeostasis, promote Aβ production, and worsen neuronal functional injury.

Numerous studies have confirmed that HIF‐1 is involved in the pathological processes of multiple CNS‐related diseases (e.g., intracranial atherosclerosis, stroke, neurodegenerative diseases)  ¹⁸¹ , ¹⁸² and has become a potential therapeutic target for neurodegenerative diseases. ¹⁸³

5.2. Crosstalk mechanism between oxidative stress and neuroinflammation

Chronic high‐altitude hypobaric hypoxia activates the HIF pathway, inducing oxidative stress ¹⁸⁴ and mitochondrial dysfunction; it also activates the NF‐κB/NLRP3 inflammatory pathway to drive neuroinflammation. ¹⁸⁵ These two processes form crosstalk via direct and indirect pathways, synergistically exacerbating CNS injury.

High‐altitude hypoxic exposure disrupts the body's oxidant‐antioxidant balance, ¹⁸⁶ specifically manifesting as intense oxidative stress and inflammatory responses ¹⁷³ , ¹⁸⁷ —this is considered the initiating factor for high‐altitude maladaptation and a series of chronic high‐altitude diseases. Its core molecular mechanism is as follows: chronic high‐altitude hypobaric hypoxia triggers oxidative stress imbalance; ROS, (e.g., superoxide anions, hydrogen peroxide) are overproduced via pathways such as mitochondrial complex III and NADPH oxidase, while the function of enzymatic (e.g., superoxide dismutase) and non‐enzymatic (e.g., glutathione) antioxidant systems is impaired, disrupting redox homeostasis. ¹⁸⁸

The damaging effects of oxidative stress on the VIN network are specifically manifested in three dimensions: Immune dimension: ROS directly activate microglia, ¹⁸⁹ induce the release of pro‐inflammatory factors (e.g., IL‐6, TNF‐α), and exacerbate neuroinflammation; Vascular dimension: Damage vascular endothelial cells, increase vascular permeability, induce high‐altitude cerebral edema and high‐altitude pulmonary edema; simultaneously induce vascular constriction, worsening cerebral hypoperfusion; Neuronal dimension: ROS directly damage neuronal DNA, lipids, and proteins, inducing neuronal apoptosis; disrupt BBB integrity, indirectly leading to neurological dysfunction such as cognitive impairment and behavioral abnormalities. ¹⁷⁵

Existing studies have confirmed that free radical scavengers exhibit significant anti‐hypoxic activity: they can effectively clear excess free radicals and reduce ROS production, thereby protecting the body from oxidative damage induced by high‐altitude hypoxia ¹⁹⁰ ; enhancing autophagy activity can alleviate oxidative stress and neurological deficits after hypobaric hypoxic exposure ¹⁹¹ ; in addition, various high‐altitude medicinal plants and their bioactive compounds play important roles in preventing diseases induced by oxidative stress. ¹⁹² , ¹⁹³ , ¹⁹⁴

5.3. Core mediating pathways, and pathological effects of neuroinflammation

Under long‐term chronic high‐altitude exposure, the HIF‐NF‐κB pathway plays a pivotal role in the transcriptional regulation of hypoxia and inflammation; even in the absence of infectious factors, multiple inflammatory mediators are abnormally upregulated, ¹⁷³ including IL‐1β, IL‐2, IL‐3, IL‐6, TNF‐α, and CCL2. ⁷⁵ , ¹⁹⁵ Neuropathological examinations show that the neurovascular network in the corpus callosum of individuals with long‐term high‐altitude exposure is significantly expanded, accompanied by microglial activation and demyelination; RNA sequencing results confirm that transcriptomic signaling pathways in the hippocampus and amygdala are altered, and these pathways are mainly related to angiogenesis, neuroinflammation, and myelin formation. ¹³³ Additionally, chronic high‐altitude hypobaric hypoxic exposure can induce overexpression of glutamate and its receptors, triggering excitotoxicity and ultimately leading to neuronal necrosis. ¹⁹⁶

In summary, the core mechanism of CNS pathological injury under chronic high‐altitude exposure is the interactive driving of the HIF pathway, oxidative stress, and neuroinflammation: the HIF pathway serves as the core regulatory hub, mediating the activation of oxidative stress and neuroinflammation; oxidative stress amplifies inflammatory responses by directly damaging cellular components and regulating HIF activity; neuroinflammation further activates the HIF pathway by exacerbating oxidative stress and vascular‐neuronal injury. These three form an irreversible pathological cycle, ultimately causing a series of injuries (e.g., BBB disruption, neuronal apoptosis, cognitive impairment), laying the pathological foundation for the occurrence and poor prognosis of high‐altitude ICH (Figure 3).

Figure 3.

Molecular pathological network of intracerebral hemorrhage (ICH) Induced by chronic high‐altitude exposure. This diagram illustrates the multi‐pathway, interactive molecular cascade underlying ICH susceptibility and poor prognosis in chronic high‐altitude (hypobaric hypoxia) exposure: 1). Initiating trigger: Chronic hypobaric hypoxia activates the hypoxia‐inducible factor (HIF) pathway, which is the core regulatory hub of this network. 2). HIF pathway dysregulation: Hypoxia drives HIF subtype imbalance, characterized by adaptive activation of HIF‐2α (inducing vascular remodeling and polycythemia) and pathological excessive activation of HIF‐1α (promoting vascular endothelial growth factor [VEGF] overexpression). 3). Damage amplification: Hypoxia also induces reactive oxygen species (ROS) overproduction and antioxidant capacity impairment, which synergistically trigger oxidative stress (injury amplifier). 4). Pathological crosstalk: The HIF pathway, oxidative stress, and their downstream effects (e.g., VEGF overexpression, polycythemia) converge to drive neuroinflammation activation and proinflammatory cytokine release, forming a vicious cycle. 5). Terminal pathological events: The integrated effects of the above cascades lead to three key pathological outcomes: BBB disruption, immune activation, and neurodegeneration. 6). Final clinical consequence: These pathological events synergistically increase ICH susceptibility and worsen prognosis (manifested as larger hematoma, severe edema, neurofunctional deficit, and high mortality). BBB, blood‐brain barrier.

6. THERAPEUTIC STRATEGIES FOR INTRACEREBRAL HEMORRHAGE AFTER CHRONIC HIGH‐ALTITUDE EXPOSURE

The pathological mechanism of ICH after chronic high‐altitude exposure is distinctive, characterized by hypoxia‐mediated excessive HIF pathway activation, interactive amplification of oxidative stress and neuroinflammation, and crosstalk of the “vascular injury‐immune infiltration‐neurodegeneration” cascade. Therefore, its treatment should follow the principle of “targeting core pathological pathways, stratified intervention, and balancing adaptation and injury repair.” Below, we systematically elaborate on key therapeutic strategies based on existing evidence:

6.1. Targeted blockade of core molecular pathways

The core pathological injury of ICH after chronic high‐altitude exposure centers on excessive HIF‐1α pathway activation, which cascades to oxidative stress, neuroinflammation, and BBB disruption; targeted blockade of this pathway and its downstream effects is thus a therapeutic priority.

As a core regulatory molecule, HIF‐1α expression is closely associated with BBB inflammatory injury, thereby influencing the formation of perihematomal edema after ICH. ¹⁹⁷ At 3 days post‐ICH onset, HIF‐1α expression levels are positively correlated with the degree of BBB inflammatory injury, ¹⁹⁸ and inhibiting HIF‐1α expression can significantly reduce various pathological injury indices in rat ICH models. Targeted intervention strategies for HIF‐1α have been proven effective: Normobaric oxygen therapy can inhibit the expression of HIF‐1α and VEGF in perihematomal tissue, alleviating neurological deficits; Hyperbaric oxygen therapy exerts effects via multiple mechanisms, including improving the ischemic‐hypoxic microenvironment, promoting VEGF‐mediated angiogenesis, enhancing the anti‐neuronal apoptosis effect of erythropoietin, balancing autophagy to avoid excessive injury, and inhibiting MMP‐9 activity to protect BBB integrity; Electroacupuncture can promote cerebral blood flow recovery after subarachnoid hemorrhage (SAH), alleviate cerebral vasospasm, and accelerate cognitive impairment recovery—its mechanism may be related to inhibition of the HIF‐1α signaling pathway ¹⁹⁹ ; Stellate ganglion block improves central post‐stroke pain complicated by anxiety and depression by inhibiting the HIF‐1α/NLRP3 signaling pathway after thalamic hemorrhagic stroke. ²⁰⁰

Notably, the HIF‐1α pathway exhibits bidirectional regulatory characteristics after SAH: it primarily promotes injury in the early stage but may have potential protective effects in the later stage, with its core mechanism closely related to early brain injury, neuroinflammation, and vascular dysfunction after SAH. ²⁰¹ Additionally, serum HIF‐1α levels have important clinical significance: after aneurysmal subarachnoid hemorrhage, elevated serum HIF‐1α levels are independently associated with delayed cerebral ischemia and poor outcomes at 6 months, serving as a potential prognostic biomarker ²⁰² ; in ICH patients, serum HIF‐1α levels are also closely associated with disease severity and poor 90‐day prognosis, providing important references for clinical assessment. ²⁰³ Given the limited high‐quality randomized controlled trials in high‐altitude ICH, current therapeutic recommendations are primarily based on pathophysiological mechanisms and clinical observational studies. Future prospective trials are needed to validate these strategies.

6.2. Comprehensive therapeutic strategies and stratified management

6.2.1. Pharmacological therapy

Carbonic anhydrase inhibitors (e.g., acetazolamide): By inhibiting carbonic anhydrase in renal and endothelial cells, these agents enhance ventilatory function while reducing hemoglobin concentration in early high‐altitude‐exposed individuals. ²⁰⁴ As classic therapeutic drugs for acute/CMS, ²⁰⁵ , ²⁰⁶ they can indirectly reduce risk factors for high‐altitude ICH (e.g., blood hyperviscosity). Corticosteroids play a crucial role in the prevention and treatment of acute mountain sickness due to their ability to regulate immune cells, protect the BBB, and alleviate cerebral edema ²⁰⁷ , ²⁰⁸ ; they also have promising therapeutic potential in recurrent acute ICH following long‐term chronic high‐altitude exposure. ²⁰⁹

Antioxidants and metabolic modulators: The oral antioxidant edaravone can protect against cognitive deficits induced by chronic high‐altitude hypobaric hypoxia. ²¹⁰ Nicotinamide riboside alleviates hypoxia‐induced neurotoxic injury in the hippocampal CA1 region by reducing microglial activation and mtROS production ¹⁶² ; upregulation of the PI3K/mTOR pathway in oligodendrocytes can mitigate Rps29‐bax‐mediated ribosomal stress and oxidative phosphorylation impairment, promote cell survival and myelin repair, and support neuronal protection. ²¹¹ Brain and muscle arnt like 1 (BMAL1) regulation targets Fis1‐mediated mitochondrial unfolded protein response, which reduces monocyte inflammatory responses and indirectly alleviates neuroinflammation. ²¹² Pharmacological inhibition of mitochondrial fission reduces microglia‐mediated synaptic elimination, thereby alleviating memory impairment in mice induced by simulated high‐altitude exposure. ²¹³

Natural drugs, with the advantages of multi‐component and multi‐target properties, have unique value in the treatment of high‐altitude ICH ²¹⁴ , ²¹⁵ ; their mechanisms of action mainly focus on antioxidation, anti‐ferroptosis, BBB repair, and neuroinflammation inhibition: Hydroxychloroquine prevents high‐altitude cerebral edema formation by inhibiting autophagic degradation of Claudin‐5 in endothelial cells. ²¹⁶ Orexin A improves high‐altitude‐induced memory retrieval impairment via the BDNF/TrkB and PI3K/AKT/mTOR signaling pathways. ²¹⁷ 6‐Hydroxygenistein alleviates high‐altitude brain injury by activating the PI3K/AKT signaling pathway. ²¹⁸ Novel rhodioloside derivatives can act as potent HIF‐1α signal inhibitors for the treatment of high‐altitude cerebral edema. ²¹⁹ Ligustrazine hydrochloride exerts a ferroptosis‐preventing effect in a rat model of high‐altitude cerebral edema by activating the NRF2 signaling pathway. ²²⁰ Notably, natural drugs have been confirmed to exert therapeutic effects in ICH via mechanisms such as antioxidation, anti‐ferroptosis, and BBB repair, ²²¹ and thus hold broad application prospects in the prevention and treatment of high‐altitude ICH.

6.2.2. Physical therapy and environmental intervention

Oxygen therapy is a key therapeutic measure for acute/CMS and critical illnesses in high‐altitude environments. ¹⁷⁷ , ²²² Hyperbaric oxygen therapy has favorable effects on ICH in high‐altitude environments ²²³ : it not only alleviates acute injury after ICH, ²²⁴ but also improves cerebral blood volume and cerebral blood flow in post‐operative patients with hypertensive ICH in high‐altitude environments, thereby enhancing their prognosis. ²²⁵ Similar to hyperbaric oxygen therapy, evacuation from high‐altitude (when conditions permit) has long been a preferred method for treating various high‐altitude critical illnesses (including high‐altitude ICH). ²²⁶ , ²²⁷ This approach eliminates hypobaric hypoxic stress at its source, reducing the continuous amplification of pathological injury—particularly the impact of the hypobaric environment. A cohort study investigating the effects of three distinct interventions (relocation to low‐altitude areas; nocturnal oxygen supplementation; acetazolamide administration) on changes in total hemoglobin levels in patients with CMS revealed that relocation to low‐altitude areas is a rapid and effective approach for treating erythrocytosis in patients with CMS. ⁶⁸ Therefore, it can be inferred that relocation to low‐altitude areas remains the optimal rehabilitation strategy for ICH occurring in high‐altitude environments.

6.3. Risk stratification‐based personalized management

Prognosis of ICH after chronic high‐altitude exposure is closely associated with CMS scores and hemoglobin concentrations: higher hemoglobin levels and CMS scores correlate with more severe ICH and poorer patient prognosis. Thus, personalized stratified management is critical for improving treatment outcomes.

First, risk monitoring and early intervention: For populations residing long‐term in high‐altitude regions (especially those diagnosed with CMS via physical examination), regular monitoring of blood pressure, hemoglobin concentration, uric acid, and lipid levels is required to alert for ICH risk. ²²⁸ The symptom characteristics adopted by the Qinghai CMS scoring system are associated with specific cognitive impairments in long‐term high‐altitude migrants; this supports using the system to monitor cognitive status in both patients with CMS and non‐CMS individuals, providing a basis for early intervention. Additionally, for Han populations in different altitude regions, an adjusted hemoglobin threshold of 200 g/L (instead of 210 g/L) is more applicable for CMS diagnosis. ⁵⁴

Second, personalized treatment adjustment: Clinical treatment requires detailed inquiry into patients’ high‐altitude exposure and CMS history; for ICH patients with concurrent CMS, potential risks (severe cerebral edema, rebleeding, poor prognosis) should be predicted in advance. Treatment plans need targeted adjustments: Surgical approach: If hematoma volume is large or edema progresses rapidly, surgical indications can be appropriately expanded, prioritizing minimally invasive hematoma evacuation combined with decompressive craniectomy. ²²⁹ , ²³⁰ , ²³¹ Pharmacotherapy: Strengthen combined use of HIF‐1α pathway inhibitors, antioxidants, and anti‐inflammatory drugs, while controlling hemoglobin within a reasonable range to avoid blood hyperviscosity worsening cerebral hypoperfusion. Long‐term rehabilitation: Develop targeted training programs based on cognitive impairment characteristics to improve neurological prognosis. For high‐altitude migrants (who are more prone to hypertension ⁹⁶ , ⁹⁷ ), targeted blood pressure monitoring, blood pressure control, oxygen supplementation, and inflammation inhibition may be critical for ICH patients in high‐altitude regions. ⁹

7. CONCLUSIONS

Long‐term chronic high‐altitude exposure‐induced ICH is a significant health challenge with distinct environmental specificity and pathological complexity. The clinical manifestations of elevated incidence, aggressive disease course, and unfavorable prognosis are tightly linked to systemic pathological remodeling caused by hypobaric hypoxia. By synthesizing epidemiological profiles, risk factors, pathological underpinnings, and core mechanisms of high‐altitude ICH, this review elucidates a key pathological network: chronic hypoxia drives HIF pathway dysregulation, and synergistic activation of oxidative stress and neuroinflammation, which together precipitate a self‐reinforcing cycle of vascular damage‐immune cell infiltration‐neuronal degeneration (Figure 4).

Figure 4.

Comparative pathological features of intracerebral hemorrhage (ICH) in plain versus high‐altitude environments. This dual‐panel diagram contrasts the pathological manifestations and severity of ICH between plain and high‐altitude settings: Upper panel (ICH in Plain): Represents ICH under plain environmental conditions. Before ICH onset, the BBB remains relatively intact; vascular constituent cells (pericytes, endothelial cells), glial cells (astrocytes, microglia), and immune cells exhibit minimal activation; the ICH lesion is relatively confined, and neurons maintain structural integrity. Lower panel (ICH in High‐altitude): Illustrates the exacerbated ICH pathology induced by chronic high‐altitude exposure: 1). Vascular and barrier dysfunction: Chronic hypobaric hypoxia drives BBB disruption and widespread activation of endothelial cells, pericytes, and glial cells (astrocytes, microglia); 2). Hematological and immune alterations: High‐altitude polycythemia (increased red blood cell count) and immune cell activation further destabilize the vascular microenvironment; 3). Severe ICH and neuronal damage: The synergistic effects of barrier disruption, cell activation, and hematological changes result in more severe ICH lesions, accompanied by widespread neuronal degeneration. This contrast demonstrates that chronic high‐altitude exposure remodels the brain microenvironment (vascular‐barrier‐immune network, [VIN]), which is the key pathological basis for the increased severity and poor prognosis of ICH in high‐altitude populations. BBB, blood‐brain barrier.

CMS and its comorbidities (HAPC, high‐altitude hypertension, high‐altitude hyperuricemia) are established as pivotal risk factors for high‐altitude ICH, whereas crosstalk‐mediated remodeling of the VIN serves as the fundamental pathological substrate. Specifically, the imbalance between maladaptive overactivation of HIF‐1α and adaptive activation of HIF‐2α functions as a central regulatory hub connecting hypoxic exposure to ICH pathogenesis, by modulating VEGF expression, oxidative stress cascades, and inflammatory responses. Oxidative stress, acting as an injury amplifier, engages in a feedforward loop with neuroinflammation, further compromising BBB integrity and aggravating neuronal injury.

While high‐altitude indigenous populations exhibit partial resistance to hypoxic damage via genetic and physiological adaptations, migrant populations face heightened risks of accelerated aging and CMS, which cannot be overlooked. Contemporary therapeutic approaches have evolved from empirical symptom control to targeted modulation of core pathological pathways, including HIF‐1α pathway inhibition, antioxidant and anti‐inflammatory interventions, and personalized stratified management, offering novel strategies to ameliorate high‐altitude ICH outcomes. Nevertheless, substantial knowledge gaps remain in the molecular mechanisms underlying high‐altitude ICH, such as the dynamic regulation of HIF subtypes, gene‐environment interactions at genetic susceptibility loci, and precise molecular targets for mitigating neuroinflammation and vascular injury. Future investigations should leverage multi‐omics technologies and prospective clinical cohorts to fill these voids.

This review presents A integration of advances in high‐altitude ICH research, laying a theoretical foundation for mechanistic studies and clinical translational practices. Further elucidation of hypoxia adaptation and injury mechanisms will facilitate the development of tailored prophylactic and therapeutic strategies, ultimately alleviating the disease burden of ICH in high‐altitude areas and enhancing healthcare for high‐altitude residents.

AUTHOR CONTRIBUTIONS

Rongsu Huang: Conceptualization; visualization; writing—original draft. Linjie Wei: Conceptualization; visualization; writing—original draft. Mingxi Li: Writing—original draft. Bo Wu: Writing—original draft. Rongjian Ouyang: Writing—original draft. Gang Zhu: Conceptualization; funding acquisition; project administration; resources; supervision; writing—review and editing. Yujie Chen: conceptualization; funding acquisition; project administration; resources; supervision; writing—review and editing.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

The authors have nothing to report.

Huang R, Wei L, Li M, et al. Chronic high‐altitude exposure and intracerebral hemorrhage: a novel perspective from the vascular‐immune‐neuronal network. Neuroprotection. 2026;1‐23. 10.1002/nep3.70059

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.