The endothelium is a complex organ that, besides providing a selectively permeable barrier, contributes to the regulation of vascular tone and vascular remodeling, oxidative homeostasis, and the immune response. Acute exposure to hypoxia results in a decrease in the endothelial release of vasorelaxant factors such as nitric oxide (NO) and an increase in the production of vasoconstrictors such as endothelin-1. This imbalance in mediators of vascular tone, combined with alterations in endothelial cell (EC) permeability, is thought to play a key role in the pathogenesis of acute mountain sickness (AMS) (1), high-altitude cerebral edema (HACE) (1), and high-altitude pulmonary edema (HAPE) (2). Besides changes in the regulation of vascular tone, alterations in endothelial function at high altitude may be associated with increased levels of oxidative stress and inflammation. Finally, the endothelium appears to be important in mediating the changes in blood vessel structure that occur as a result of chronic exposure to high altitude.

ACUTE RESPONSE TO HYPOXIA

The major physiological consequence of exposure to acute hypoxia and high altitude is organ-specific vasoconstriction (3). Within the pulmonary vascular bed, for example, hypoxia-induced vasoconstriction is an important mechanism for matching ventilation and perfusion. A dysfunctional endothelial response, however, may lead to exaggerated vasoconstriction, alterations in regional blood flow, and ventilation-perfusion mismatches. Moreover, an exaggerated hypoxic vasoconstrictor response may lead to capillary stress failure, alterations in EC permeability, and ultimately tissue edema.