The ability of cells to tolerate hypoxia is critical to their survival, but varies greatly among different cell types. Despite alterations in many cellular responses during hypoxic exposure, pulmonary arterial endothelial cells (PAEC) retain their viability and cellular integrity. Under similar experimental conditions, other cell types, exemplified by renal tubular epithelial cells, are extremely hypoxia sensitive and are rapidly and irreversibly damaged. To investigate potential mechanisms by which PAEC maintain cellular and functional integrity under these conditions, we compared the turnover of adenine and guanine nucleotides in hypoxia tolerant PAEC and in hypoxia-sensitive renal tubular endothelial cells under various hypoxic conditions. Under several different hypoxic conditions, hypoxia-tolerant PAEC maintained or actually increased ATP levels and the percentage of these nucleotides found in the high energy phosphates, ATP and GTP. In contrast, in hypoxia-sensitive renal tubular endothelial cells, the same high energy phosphates were rapidly depleted. Yet, in both cell types, there were minor alterations in the uptake of the precusor nucleotide and its incorporation into the appropriate purine nucleotide phosphates and marked decreases in ATPase and GTPase activity. This maintenance of high energy phosphates in hypoxic PAEC suggests that there exists tight regulation of ATP and GTP turnover in these cells and that preservation of these nucleotides may contribute to the tolerance of PAEC to acute and chronic hypoxia. (J. Clin. Invest. 1995. 95:738-744.)

We have previously reported alterations in cyclooxygenase metabolism in cultured aortic and pulmonary arterial endothelial cells exposed to acute and chronic hypoxia. These alterations depended on the duration and degree of the hypoxic exposure, on the vascular bed from which the endothelial cells were derived, and possibly on the availability of arachidonic acid secondary to modifications in metabolic substrate, membrane phospholipids, and/or membrane phospholipase activity. To investigate this last point further, we have compared plasma membrane phospholipid distribution and phospholipase activity in cultured aortic and pulmonary arterial endothelial cells exposed to both acute and chronic hypoxia, using two different precursors (acetic acid and arachidonic acid) and three different membrane preparations (cell homogenates, partially purified plasma membranes, and highly purified plasma membranes). We found that exposure to acute and chronic hypoxia has profound and complicated effects on endothelial cell phospholipid composition and phospholipase activity and that these effects depend on the origin of the endothelial cells and the duration of hypoxia. Furthermore, we found that the alterations in endothelial cell phospholipid distribution in response to hypoxia depend on the purity of the plasma membrane preparation and the metabolic precursor used to study phospholipid metabolism. Finally, these studies suggested that alterations in phospholipids during hypoxia occurred to a greater extent in compartments of endothelial cells other than the plasma membranes and that the well-recognized tolerance of endothelial cells to hypoxia may be due, in part, to preservation of the integrity of their plasma membranes during exposure to acute and chronic hypoxia.

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