Open AccessTIE2‐expressing monocytes/macrophages regulate revascularization of the ischemic limb
Author(s) -
Patel Ashish S.,
Smith Alberto,
Nucera Silvia,
Biziato Daniela,
Saha Prakash,
Attia Rizwan Q.,
Humphries Julia,
Mattock Katherine,
Grover Steven P.,
Lyons Oliver T.,
Guidotti Luca G.,
Siow Richard,
Ivetic Aleksandar,
Egginton Stuart,
Waltham Matthew,
Naldini Luigi,
De Palma Michele,
Modarai Bijan
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201302752
Subject(s) - arteriogenesis , angiopoietin receptor , ischemia , neovascularization , hindlimb , revascularization , medicine , angiogenesis , peripheral blood mononuclear cell , cancer research , in vitro , biology , myocardial infarction , biochemistry
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.