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-mediated angiogenesis
Departments of 1Radiation Oncology, 2Cell Biology, and 3Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Submitted 24 November 2003 ; accepted in final form 19 February 2004
Inflammation and angiogenesis are associated with pathological disorders. TNF-
is a major inflammatory cytokine that also regulates angiogenesis. TNF-
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-
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-
. In the absence of TNF-
, neither Ang-1 nor Ang-2 promoted corneal angiogenesis. Low doses (025 ng/ml) of TNF-
increased vascular branch formation of cultured endothelial cells. Overexpression of Ang-1 or Ang-2 enhanced the effects of TNF-
. These data suggest that Tie-2 signaling synergistically amplifies and participates in TNF-
-mediated angiogenesis. In addition, high doses (
50 ng/ml) of TNF-
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-
-induced angiogenesis, and high doses attenuate TNF-
-induced cell death. The study provides evidence supporting a role for Tie-2 in inflammatory angiogenesis.
inflammation; cell death
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