Journal of Applied Physiology, Vol 79, Issue 2 375-379, Copyright © 1995 by American Physiological Society

ARTICLES

Hypothetical roles of angiogenesis, osmotic swelling, and ischemia in high-altitude cerebral edema

J. W. Severinghaus
Department of Anesthesia, University of California Medical School, San Francisco 94143-0542, USA.

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 inadequate because 1) ATP decrease occurs only after anoxia has silenced neuronal 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 presented. 1) Osmotic cell swelling: cellular and mitochondrial osmotic pressure may rise 30 mosmol in ischemia or anoxia (potentially a 7-10% expansion). Smaller rises caused by hypoxia may be significant in the closed calvarium. 2) Focal ischemia: this may result from intracranial hypertension from hyperemia and osmotic swelling. 3) Angiogenesis: cellular hypoxia initially attracts and activates macrophages that express vascular endothelial growth factor and other cytokines, dissolving capillary basement membranes and degrading extracellular matrix, resulting in capillary leakage. In HACE, petechial hemorrhages are seen in the nerve cell layers of the retina, and similar changes have been described throughout the brain. Evidence linking HACE to angiogenesis is that dexamethasone, an effective inhibitor of angiogenesis, has demonstrated unique success in preventing and treating HACE.

This article has been cited by other articles:

				C. Clarke Neurology at high altitude Practical Neurology, August 1, 2006; 6(4): 230 - 237. [Full Text] [PDF]

				H. J. Schoch, S. Fischer, and H. H. Marti Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain Brain, November 1, 2002; 125(11): 2549 - 2557. [Abstract] [Full Text] [PDF]

				J G Jones The Hypoxia Hilton: recollections of a visit, with a postscript by J W Severinghaus on mechanisms of acute mountain sickness J R Soc Med, January 12, 2002; 95(12): 606 - 608. [Full Text] [PDF]

				P. H. Hackett and R. C. Roach High-Altitude Illness N. Engl. J. Med., July 12, 2001; 345(2): 107 - 114. [Full Text] [PDF]

				D. H. Munzenmaier and D. R. Harder Cerebral microvascular endothelial cell tube formation: role of astrocytic epoxyeicosatrienoic acid release Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1163 - H1167. [Abstract] [Full Text] [PDF]

				S.-F. Yan, N. Mackman, W. Kisiel, D. M. Stern, and D. J. Pinsky Hypoxia/Hypoxemia-Induced Activation of the Procoagulant Pathways and the Pathogenesis of Ischemia-Associated Thrombosis Arterioscler Thromb Vasc Biol, September 1, 1999; 19(9): 2029 - 2035. [Abstract] [Full Text] [PDF]

				P. H. Hackett, P. R. Yarnell, R. Hill, K. Reynard, J. Heit, and J. McCormick High-Altitude Cerebral Edema Evaluated With Magnetic Resonance Imaging: Clinical Correlation and Pathophysiology JAMA, December 9, 1998; 280(22): 1920 - 1925. [Abstract] [Full Text] [PDF]

				F. Xu and J. W. Severinghaus Rat brain VEGF expression in alveolar hypoxia: possible role in high-altitude cerebral edema J Appl Physiol, July 1, 1998; 85(1): 53 - 57. [Abstract] [Full Text] [PDF]