Tie2 Receptor Expression Is Stimulated by Hypoxia and Proinflammatory Cytokines in Human Endothelial Cells

Abstract

The tyrosine kinase receptor Tie2 (also known as Tek) plays an important role in the development of the embryonic vasculature and persists in adult endothelial cells (ECs). Tie2 was shown to be upregulated in tumors and skin wounds, and its ligands angiopoietin-1 and -2, although they are not directly 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 processes, on Tie2 expression in human ECs. Exposure to 1% O(2) led to a time-dependent significant rise of Tie2 protein levels in human coronary microvascular endothelial cells (HCMECs) and dermal microvascular ECs (HMEC-1) (3.2- and 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-fold). Hypoxia-conditioned medium and D-deoxyglucose did not change Tie2 expression, but desferrioxamine and cobalt, which are known to mimic hypoxia-sensing mechanisms, induced Tie2 at ambient oxygen tensions. Tumor necrosis factor-alpha induced Tie2 in a time- and dose-dependent fashion in all 3 EC types (HUVEC, 2.3-fold; HMEC-1, 2. 8-fold; and HCMEC, 3.0-fold; 10 ng/mL, 24 hours). Enhanced expression was also found after exposure to interleukin-1beta (1 ng/mL). Changes in Tie2 protein levels were paralleled by changes in mRNA expression. In accordance with these in vitro findings, immunohistochemistry revealed focal upregulation of Tie2 in capillaries at the border of infarcted human and rat myocardium. In conclusion, the data show that hypoxia and inflammatory cytokines upregulate Tie2, which may contribute to the angiogenic response in ischemic tissues.

Identification of Progenitor Cells That Contribute to Heterotopic Skeletogenesis

“…Interestingly, misexpression of constitutively active ACVR1/ALK2, a BMP type-I receptor and the gene mutated in fibrodysplasia ossificans progressiva, is sufficient to stimulate an endothelialto-mesenchymal transformation in endothelial cells of the heart 41 . Notably, BMP4, as well as hypoxia and inflammatory cytokines-conditions and factors that are present in the earliest preosseous lesions of heterotopic ossification-upregulate Tie2 in endothelial cells, which contributes to the angiogenic response 39,42 . The ongoing expression of Tie2 and other endothelial markers at all stages of BMP-induced ossification is likely a response to these local environmental cues and is entirely consistent with previous reports in two animal models of bone regeneration and fracture callus formation 43 .…”

Impaired VE-Cadherin/β-Catenin Expression Mediates Endothelial Cell Degeneration in Dilated Cardiomyopathy

“…In addition, increased Tie-2 levels in ICM might have been reactive to chronic hypoxia. 27 Ang-2 might allow the vessels to revert to and remain in a more plastic state, in which they may be more responsive to a sprouting signal provided by VEGF. 26 Whether downregulated Ang-2 expression is adaptive to blunted VEGF expression 5 remains uncertain.…”

Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis

“…Induction and up-regulation of TIE-2 and ANG-2 expression in endothelial cells are regulated by hypoxia and proinflammatory cytokines, such as tumor necrosis factor-a and interleukin1h (68,(118)(119)(120)(121)(122). Conversely, such stimuli down-regulate the expression of ANG-1 (66,67), suggesting a delicate inverse relationship between ANG-1 and ANG-2 in the regulation of TIE-2 signaling.…”