Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis

Am J Pathol. 2006 Nov;169(5):1886-98. doi: 10.2353/ajpath.2006.060603.


We have previously shown that tumor necrosis factor (TNF) acts via its two receptors TNFR1 and TNFR2 to elicit distinct signaling pathways in vascular endothelial cells (ECs). Here we used a femoral artery ligation model to demonstrate that TNFR1-knockout (KO) mice had enhanced, whereas TNFR2-KO had reduced, capacity in clinical recovery, limb perfusion, and ischemic reserve capacity compared with the wild-type mice. Consistently, ischemia-initiated collateral growth (arteriogenesis) in the upper limb and capillary formation and vessel maturation (angiogenesis) in the lower limb were enhanced in TNFR1-KO but were reduced in TNFR2-KO mice. Furthermore, our results suggest that vascular proliferation, but not infiltration of macrophages and lymphocytes, accounted for the phenotypic differences between the TNFR1-KO and TNFR2-KO mice. In wild-type animals TNFR2 protein in vascular endothelium was highly up-regulated in response to ischemia, leading to increased TNFR2-specific signaling as determined by the formation TNFR2-TRAF2 complex and activation of TNFR2-specific kinase Bmx/Etk. In isolated murine ECs, activation of TNFR2 induced nuclear factor-kappaB-dependent reporter gene expression, EC survival, and migration. In contrast, activation of TNFR1 caused inhibition of EC migration and EC apoptosis. These data demonstrate that TNFR1 and TNFR2 play differential roles in ischemia-mediated arteriogenesis and angiogenesis, partly because of their opposite effects on EC survival and migration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arteries / embryology*
  • Blood Vessels
  • Cattle
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Endothelial Cells / cytology
  • Endothelial Cells / pathology
  • Endothelium, Vascular / pathology
  • Hindlimb / cytology
  • Hindlimb / pathology
  • Humans
  • Ischemia / chemically induced*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Neovascularization, Pathologic*
  • Organogenesis*
  • Perfusion
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / chemistry
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Signal Transduction*
  • TNF Receptor-Associated Factor 2 / metabolism


  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • TNF Receptor-Associated Factor 2
  • BMX protein, human
  • Protein-Tyrosine Kinases