Neurovascular mechanisms of high-altitude retinopathy and the potential therapeutic relevance of natural compounds

High-altitude retinopathy (HAR) is usually described by fundus changes after ascent. That definition misses the biological problem that makes HAR worth studying: hypobaric hypoxia stresses two separate ocular circulations at once, along with a metabolically demanding neural tissue and a blood–retinal barrier (BRB) that maintains fluid balance. The response may stay a reversible vascular adjustment, or it may progress to hemorrhage, macular injury, and visual dysfunction. Optical coherence tomography angiography (OCTA), functional OCT and electroretinography (ERG) show that vascular and neural response scan diverge: perfusion-related compensation may persist while retinal function declines, and the two may recover on different time scales after reoxygenation. The high-altitude retinal response is therefore better viewed as an adaptation–mismatch–decompensation spectrum than as a linear cascade from hypoxia to cell death. In this Review, reversible vascular or metabolic adjustment without barrier failure, structural injury or persistent functional loss is termed physiological adaptation; HAR is reserved for pathological retinal findings attributable to altitude. This Review examines HAR at three linked levels: clinical differential diagnosis, the retinal neurovascular unit, and the potential therapeutic relevance of natural compounds and extracts. We distinguish reversible vascular adjustment from neurovascular mismatch, barrier failure and regulated cell death. We summarize current medical management without extrapolating general altitude-illness drugs to unproven retinal indications, and we assess chemically defined natural compounds and extracts using a defined evidence hierarchy. Salidroside from a well-characterized Rhodiola tangutica extract, resveratrol, and hesperidin have direct high-altitude retinal data, but the evidence remains preclinical. Studies in other retinal hypoxia or ischemia models point to mechanisms involving mitochondrial quality control, ferroptosis, NLRP3 signaling, endothelial junctions, and glial metabolism; they do not establish efficacy in HAR. Progress will require longitudinal multimodal human phenotyping, standardized hypobaric models, retinal pharmacokinetics, causal target engagement and trials designed around exposure, susceptibility, and recovery.