HYPOTHETICAL ROLES OF ANGIOGENESIS, OSMOTIC SWELLING, AND ISCHEMIA INHIGH-ALTITUDE CEREBRAL EDEMA

High-altitude cerebral edema (HACE) has been tentatively attributed to either cellular ion pump failure from ATP depletion or high cerebral blood flow inducing high capillary pressure. These hypotheses are inad equate because 1) ATP decrease occurs only after anoxia has silenced n euronal activity and 2) prolonged hypercapnic hyperemia generates only minor transcapillary protein leakage localized to the less hyperemic brain regions. In connection with this review of HACE and its causes, three other hypothetical mechanisms that might contribute are presente d. 1) Osmotic cell swelling: cellular and mitochondrial osmotic pressu re may rise 30 mosmol in ischemia or anoxia (potentially a 7-10% expan sion). Smaller rises caused by hypoxia may be significant in the close d calvarium. 2) Focal ischemia: this may result from intracranial hype rtension from hyperemia and osmotic swelling. 3) Angiogenesis: cellula r hypoxia initially attracts and activates macrophages that express va scular endothelial growth factor and other cytokines, dissolving capil lary basement membranes and degrading extracellular matrix, resulting in capillary leakage. In HACE, petechial hemorrhages are seen in the n erve cell layers of the retina, and similar changes have been describe d throughout the brain. Evidence linking HACE to angiogenesis is that dexamethasone, an effective inhibitor of angiogenesis, has demonstrate d unique success in preventing and treating HACE.