Dual functional roles of Tie-2/angiopoietin in TNF-α-mediated angiogenesis

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Abstract
Inflammation and angiogenesis are associated with pathological disorders. TNF-α is a major inflammatory cytokine that also regulates angiogenesis. TNF-α has been shown to regulate Tie-2 and angiopoietin (Ang) expression, but the functional significance is less clear. In this study, we showed that TNF-α induced a weak angiogenic response in a mouse cornea assay. Systemic overexpression of Ang-1 or Ang-2 dramatically increased corneal angiogenesis induced by TNF-α. In the absence of TNF-α, neither Ang-1 nor Ang-2 promoted corneal angiogenesis. Low doses (0–25 ng/ml) of TNF-α increased vascular branch formation of cultured endothelial cells. Overexpression of Ang-1 or Ang-2 enhanced the effects of TNF-α. These data suggest that Tie-2 signaling synergistically amplifies and participates in TNF-α-mediated angiogenesis. In addition, high doses (≥50 ng/ml) of TNF-α induced apoptosis in endothelial cells, but addition of Ang-1 or Ang-2 significantly reduced cell death. Enhanced endothelial cell survival was correlated with Akt phosphorylation. Collectively, our data reveal dual functional roles of Tie-2: low doses enhance TNF-α-induced angiogenesis, and high doses attenuate TNF-α-induced cell death. The study provides evidence supporting a role for Tie-2 in inflammatory angiogenesis.