Endothelial Cell hypoxic stress proteins

The vascular endothelium is an important mediator of vascular tone, inflamm atory-immune reactions, vascular permeability, angiogenesis, and hemostasis . Endothelial functions may be altered by changes in the local cellular env ironment, particularly changes in oxygen tension. The mechanisms by which e ndothelial cells (ECs) respond and adapt to hypoxia are unknown; however, t he EC is one of the more hypoxia-tolerant mammalian cell types. Cultured EC s exposed to hypoxia up-regulate a set of stress proteins, termed hypoxia-a ssociated proteins (HAPs), that are distinct from the classically described stress proteins induced by heat shock (heat-shock proteins, HSPs) or gluco se deprivation (glucose-regulated proteins, GRPs). Two of these proteins ha ve been identified as the glycolytic enzymes glyceraldehyde-3-phosphate deh ydrogenase (GAPDH) and non-neuronal enolase (NNE). GAPDH expression during hypoxia is regulated primarily at the level of transcription, while the mec hanism of NNE mRNA accumulation remains unclear. GAPDH, NNE, and the other HAPs are up-regulated by transitional metals and deferoxamine; however, unl ike the situation with other hypoxia-regulated proteins such as erythropoie tin, the up-regulation of GAPDH, NNE, and the other HAPs by hypoxia is not inhibited by carbon monoxide. Subcellular fractionation of hypoxic EC has s hown that GAPDH and NNE are up-regulated in the cytoplasmic fraction as wou ld be expected for a glycolytic enzyme; however, a protein corresponding to GAPDH is also up-regulated in the nuclear fraction. This suggests that GAP DH and perhaps NNE have functions aside from their catalytic function in gl ycolysis. It is unknown whether the up-regulation of GAPDH, NNE, and the ot her HAPs in ECs is related to the relative ability of ECs to adapt to hypox ia; however, other more-hypoxia-sensitive cells do not up-regulate HAPs.