TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb

EMBO Mol Med. 2013 Jun;5(6):858-69. doi: 10.1002/emmm.201302752. Epub 2013 May 7.


A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2-expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed to examine the kinetics of TEMs in patients with CLI and whether these cells promote neovascularization of the ischemic limb. Here we show that there are 10-fold more circulating TEMs in CLI patients, and removal of ischemia reduces their numbers to normal levels. TEM numbers in ischemic muscle are two-fold greater than normoxic muscle from the same patient. TEMs from patients with CLI display greater proangiogenic activity than TIE2-negative monocytes in vitro. Using a mouse model of hindlimb ischemia, lentiviral-based Tie2 knockdown in TEMs impaired recovery from ischemia, whereas delivery of mouse macrophages overexpressing TIE2, or human TEMs isolated from CLI patients, rescued limb ischemia. These data suggest that enhancing TEM recruitment to the ischemic muscle may have the potential to improve limb neovascularization in CLI patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiopoietin-2 / metabolism
  • Animals
  • Female
  • Humans
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Mice
  • MicroRNAs / metabolism
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Muscle, Skeletal / blood supply
  • Muscle, Skeletal / metabolism
  • Neovascularization, Physiologic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor, TIE-2 / antagonists & inhibitors
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiopoietin-2
  • MicroRNAs
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • Receptor, TIE-2