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

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.