Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells

The tyrosine kinase receptor Tie2 (also known as Tek) plays an important ro le in the development of the embryonic vasculature and persists in adult en dothelial cells (ECs). Tie2 was shown to he upregulated in tumors and skin wounds, and its ligands angiopoietin-1 and -2, although they are not direct ly mitogenic, modulate neovascularization. To gain further insight into the regulation of Tie2, we have studied the effect of hypoxia and inflammatory cytokines, two conditions frequently associated with neoangiogenic process es, on Tie2 expression in human ECs. Exposure to 1% O-2 led to a time-depen dent significant rise of Tie2 protein levels in human coronary microvascula r endothelial cells (HCMECs) and dermal microvascular ECs (HMEC-1) (3.2- an d 2.5-fold within 24 hours), which was reversible after reoxygenation, and induced a less marked increase in human umbilical vein ECs (HUVECs; 1.7-fol d). Hypoxia-conditioned medium and D-deoxyglucose did not change Tie2 expre ssion, but desferrioxamine and cobalt, which are known to mimic hypoxia-sen sing mechanisms, induced Tie2 at ambient oxygen tensions, Tumor necrosis fa ctor-ct induced Tie2 in a time- and dose-dependent fashion in all 3 EC type s (HUVEC, 2.3-fold; HMEC-1, 2.8-fold; and HCMEC, 3.0-fold; 10 ng/mL, 24 hou rs). Enhanced expression was also found after exposure to interleukin-1 bet a (1 ng/mL). Changes in Tie2 protein levels were paralleled by changes in m RNA expression. In accordance with these in vitro findings, immunohistochem istry revealed focal upregulation of Tie?, in capillaries at the border of infarcted human and rat myocardium. In conclusion, the data show that hypox ia and inflammatory cytokines upregulate Tie2, which may contribute to the angiogenic response in ischemic tissues.