title: TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb.
abstract: 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.
authors: Academic Department of Surgery, Cardiovascular Division, King's College London, Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK.
authors: Ashish S
authors: AS
authors: Patel
authors: Alberto
authors: A
authors: Smith
authors: Silvia
authors: S
authors: Nucera
authors: Daniela
authors: D
authors: Biziato
authors: Prakash
authors: P
authors: Saha
authors: Rizwan Q
authors: RQ
authors: Attia
authors: Julia
authors: J
authors: Humphries
authors: Katherine
authors: K
authors: Mattock
authors: Steven P
authors: SP
authors: Grover
authors: Oliver T
authors: OT
authors: Lyons
authors: Luca G
authors: LG
authors: Guidotti
authors: Richard
authors: R
authors: Siow
authors: Aleksandar
authors: A
authors: Ivetic
authors: Stuart
authors: S
authors: Egginton
authors: Matthew
authors: M
authors: Waltham
authors: Luigi
authors: L
authors: Naldini
authors: Michele
authors: M
authors: De Palma
authors: Bijan
authors: B
authors: Modarai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D005260:Female; D006801:Humans; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D035683:MicroRNAs; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2
references: Cancer Cell. 2005 Sep;8(3):211-26
references: 16169466
references: Am J Pathol. 2011 Nov;179(5):2651-9
references: 21924227
references: Circulation. 2005 May 24;111(20):2645-53
references: 15883207
references: Trends Immunol. 2007 Dec;28(12):519-24
references: 17981504
references: Atherosclerosis. 2010 Mar;209(1):10-7
references: 19740466
references: Blood. 2012 Oct 11;120(15):3152-62
references: 22919031
references: Circulation. 2012 Jul 24;126(4):491-500
references: 22825411
references: Blood. 2010 Aug 5;116(5):829-40
references: 20404134
references: Mol Ther. 2009 Jun;17(6):1039-52
references: 19293777
references: Hepatology. 2013 Apr;57(4):1416-25
references: 22815256
references: Lancet. 2002 Jun 15;359(9323):2053-8
references: 12086757
references: Cancer Cell. 2011 Apr 12;19(4):512-26
references: 21481792
references: EMBO Mol Med. 2013 Jun;5(6):843-57
references: 23616286
references: J Vasc Surg. 2006 Jul;44(1):108-114
references: 16828434
references: Circulation. 2009 Dec 1;120(22):2240-50
references: 19917886
references: Lancet. 2011 Jun 4;377(9781):1929-37
references: 21621834
references: Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1989-95
references: 18772493
references: Cancer Res. 2010 Jul 1;70(13):5270-80
references: 20530679
references: Int Angiol. 2011 Feb;30(1):25-34
references: 21248670
references: Nature. 2011 Oct 09;479(7371):122-6
references: 21983962
references: Circulation. 2004 Jun 8;109(22):2692-7
references: 15184293
references: Science. 2010 Feb 5;327(5966):656-61
references: 20133564
references: Circ Res. 2007 Jul 6;101(1):88-96
references: 17540977
references: Circulation. 2009 Feb 10;119(5):699-708
references: 19171856
references: J Am Coll Cardiol. 2008 Jul 29;52(5):387-93
references: 18652948
references: Cochrane Database Syst Rev. 2011 Dec 07;(12):CD008347
references: 22161427
references: J Vasc Surg. 1992 Jul;16(1):54-9
references: 1619725
references: Circulation. 2003 Oct 21;108(16):1933-8
references: 14504183
references: J Vasc Surg. 2007 Jan;45 Suppl S:S5-67
references: 17223489
references: Blood. 2009 Jul 23;114(4):901-14
references: 19383967
references: Blood. 2011 Sep 22;118(12):e50-61
references: 21803849
references: J Vasc Surg. 2010 Jan;51(1):230-41
references: 20117502
references: Blood. 2011 Mar 17;117(11):3065-75
references: 21149635
references: Atherosclerosis. 2004 May;174(1):111-20
references: 15135259