Abstract 12860: TIE2-Expressing Monocytes/Macrophages Promote Recovery from Tissue Ischaemia
Introduction Monocytes (CD14+ cells) expressing the angiopoietin receptor, TIE2, are a highly angiogenic subset that are pivotal to neovascularisation in the environs of tumours. We hypothesise that Tie2 expressing monocytes (TEMs) are also important in neovascularisation of ischaemic tissues.
Methods and Results Flow cytometric analysis revealed a 10-fold higher number of circulating TEMs in patients with critical limb ischaemia (CLI) compared with matched controls (P<0.0001, n=40/group). Analysis by RT-PCR confirmed TIE2 mRNA expression in TEMs. Revascularisation or amputation resulted in a fall in TEM numbers to control levels (P<0.005). Circulating angiopoietin-2 levels were 2-fold higher in CLI patients compared with controls (P<0.05). Circulating CD115+/TIE2+ monocytes were higher following hindlimb ischaemia (HLI) in mice compared with sham controls (P<0.05). TIE2 expression was upregulated in CD45+/CD11b+/F4/80+ macrophages isolated from ischaemic hindlimbs (P<0.05). We used a Tie2 gene knockdown strategy to study the significance of TIE2 for TEM function in ischaemic tissues. Haematopoietic stem/progenitor cells, isolated from Pgk-rtTA-miR-126T transgenic mice, were transduced ex-vivo with a TRE-miR-Tie2-OFP lentiviral vector and used to reconstitute lethally irradiated mice. Doxycycline-induced Tie2 gene knockdown in TEMs inhibited neovascularisation of the ischaemic hindlimb in the mice (P<0.0001, Fig A). Enforced TIE2 expression in bone marrow-derived macrophages (BMDMs) accelerated the recovery of blood flow in the mouse ischaemic hindlimb compared with control BMDMs (P<0.0001, Fig B).
Conclusion Our studies suggest that: (i) TEMs are mobilised following ischaemia and contribute to the revascularisation of ischaemic tissue; (ii) TIE2 is important for the proangiogenic functions of TEMs. TEMs may therefore represent a promising, novel therapeutic target for angiogenic cell therapy in critically ischaemic tissues.
- © 2012 by American Heart Association, Inc.