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.

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…This line of study may have value in determining how both destructive and reparative processes occur through the migration of cell populations from the recipient to the donor (77,80,83). OTT also facilitates lineage fate mapping studies to track the movement and transformation of various cell types in the allograft recipient (83)(84)(85). The mouse orthotopic lung transplant model also holds promise as an effective platform for evaluating the relative contribution of recipient cells in both the disease and repair of small airways and pulmonary parenchyma.…”

Tie2 Expression on Macrophages Is Required for Blood Vessel Reconstruction and Tumor Relapse after Chemotherapy

“…Although TEMs play an important role in the angiogenesis in many tumor models, the proportion of TEMs varies in different types of tumors. Interestingly, Tie2-positive macrophages have been reported to accumulate in tumor microenvironment after chemotherapy, antiangiogenic treatment, radiotherapy, or in injured muscle tissue of ischemic limb (18,19), suggesting that TEMs are involved in vascular reconstruction. However, the exact molecular mechanism for that is still not known.…”

“…Several studies indicate that Tie2 is important for the function of TEMs, for example, as a chemotaxis receptor or adhesion receptor to endothelial cells (19)(20)(21). Many studies trying to figure out the role of Tie2 on macrophages were based on the stimulation of angiopoietins (20)(21)(22).…”

Multiple-Site Activation of the Cysteinyl Leukotriene Receptor 2 Is Required for Exacerbation of Ischemia/Reperfusion Injury

“…40 These monocytes are highly angiogenic, vital to tumor neovascularization, and are mobilized after ischemia for the revascularization of ischemic tissue. 41 Indeed, the majority of Tie2 + monocytes in mice are resident cluster of differentiation (CD)11b + Gr-1 low/neg monocytes, 42 thought to be instrumental to inflammatory response resolution, 43 therefore, it will be interesting to investigate the role of CysLT 2 R activation/overexpression in this cell population in future studies. We certainly cannot rule out the possibility that the activation of CysLT 2 R on Tie2 + myeloid cells is involved in the mechanisms explored herein.…”