Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 287, Issue 1, Pages H187-H195Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01058.2003
Keywords
inflammation; cell death
Funding
- NCI NIH HHS [CA-68485, CA-90949, T32 CA009592, CA-86283, CA-89674, CA-87756] Funding Source: Medline
- NIDDK NIH HHS [DK-20593] Funding Source: Medline
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Inflammation and angiogenesis are associated with pathological disorders. TNF-alpha is a major inflammatory cytokine that also regulates angiogenesis. TNF-alpha 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-alpha 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-alpha. In the absence of TNF-alpha, neither Ang-1 nor Ang-2 promoted corneal angiogenesis. Low doses (0-25 ng/ml) of TNF-alpha increased vascular branch formation of cultured endothelial cells. Overexpression of Ang-1 or Ang-2 enhanced the effects of TNF-alpha. These data suggest that Tie-2 signaling synergistically amplifies and participates in TNF-alpha-mediated angiogenesis. In addition, high doses (greater than or equal to50 ng/ml) of TNF-alpha 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-alpha-induced angiogenesis, and high doses attenuate TNF-alpha-induced cell death. The study provides evidence supporting a role for Tie-2 in inflammatory angiogenesis.
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