Abstract
Endothelial progenitor cells (EPCs) are a group of heterogeneous cells in bone marrow (BM) and blood. Ischaemia increases reactive oxygen species (ROS) production that regulates EPC number and function. The present study was conducted to determine if ischaemia‐induced ROS differentially regulated individual EPC subpopulations using a mouse model concomitantly overexpressing superoxide dismutase (SOD)1, SOD3 and glutathione peroxidase. Limb ischaemia was induced by femoral artery ligation in male transgenic mice with their wild‐type littermate as control. BM and blood cells were collected for EPCs analysis and mononuclear cell intracellular ROS production, apoptosis and proliferation at baseline, day 3 and day 21 after ischaemia. Cells positive for c‐Kit+/CD31+ or Sca‐1+/Flk‐1+ or CD34+/CD133+ or CD34+/Flk‐1+ were identified as EPCs. ischaemia significantly increased ROS production and cell apoptosis and decreased proliferation of circulating and BM mononuclear cells and increased BM and circulating EPCs levels. Overexpression of triple antioxidant enzymes effectively prevented ischaemia‐induced ROS production with significantly decreased cell apoptosis and preserved proliferation and significantly increased circulating EPCs level without significant changes in BM EPC populations, associated with enhanced recovery of blood flow and function of the ischemic limb. These data suggested that ischaemia‐induced ROS was differentially involved in the regulation of circulating EPC population.
Highlights
Formation of new blood vessels is an import‐ ant mechanism in response to ischemic injuries/conditions such as ischemic heart disease and peripheral artery disease.[1,2] Bone mar‐ row (BM)‐derived endothelial progenitor cells (EPCs) play a critical role in vascular re‐endothelialization, angiogenesis and prevention of neointima formation after vascular injury.[1,2] EPCs are a Lingjuan Liu and Yuqi Cui contributed to the workJ Cell Mol Med. 2019;23:4019–4029.| 4020 group of very heterogeneous cell population with a variety of differ‐ ent cell markers reported in the literature.[3]
High concentrations of Reactive oxygen species (ROS) are involved in senescence and apoptosis of endothelial cells and stem/progen‐ itor cells and associated with defective neovascularization,[9,10] low levels of ROS generated during tissue ischaemia serve as intracellu‐ lar signals to trigger angiogenesis.[11,12]
Many antioxidant enzymes including copper–zine superoxide dismutase (SOD1) in the cytoplasm,[16] extracellular SOD (SOD3)[17,18] and glutathione peroxidase (Gpx‐1) 19,20 have been indi‐ vidually reported to have a beneficial effect on the mobilization of EPCs and neovascularization after limb ischaemia
Summary
Formation of new blood vessels (neovascularization) is an import‐ ant mechanism in response to ischemic injuries/conditions such as ischemic heart disease and peripheral artery disease.[1,2] Bone mar‐ row (BM)‐derived endothelial progenitor cells (EPCs) play a critical role in vascular re‐endothelialization, angiogenesis and prevention of neointima formation after vascular injury.[1,2] EPCs are a Lingjuan Liu and Yuqi Cui contributed to the work. It has been reported that ROS production in BM derived mononuclear cells is associated with the number of EPC.[14] Many antioxidant enzymes including copper–zine superoxide dismutase (SOD1) in the cytoplasm,[16] extracellular SOD (SOD3)[17,18] and glutathione peroxidase (Gpx‐1) 19,20 have been indi‐ vidually reported to have a beneficial effect on the mobilization of EPCs and neovascularization after limb ischaemia. It has been reported that SOD overexpression could be associated with in‐ creased levels of hydrogen peroxide (H2O2) with increased oxidative stress in vitro and in vivo.[21] it is not clear if the beneficial effect of SOD overexpression on EPC and neovascularization was because of decreased ROS formation. As there were no unified cell markers for EPCs, we used four different groups of cell markers to identify EPCs to ensure a comprehensive analysis of EPCs in BM and blood
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