Dual functional roles of Tie-2/angiopoietin in TNF-alpha-mediated angiogenesis.
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 (>/=50 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.
Chen
Jian-Xiong
JX
Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave., Preston Research Bldg., Rm. 315, Nashville, TN 37232, USA.
Chen
Ying
Y
DeBusk
Laura
L
Lin
Wenyu
W
Lin
Pengnain Charles
PC
D042683:Angiopoietin-1 / Q000502:physiology*; D042702:Angiopoietin-2 / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002196:Capillaries / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D042787:Receptor, TIE-2 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D042787:Receptor, TIE-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt