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Endothelial progenitor cells augment collateralization and hemodynamic rescue in a model of chronic cerebral ischemia.

ABSTRACT: Surgical flow augmentation for treatment of cerebral hemodynamic impairment remains controversial. Here, we investigated the benefit of endothelial progenitor cell (EPC) treatment in a rat model of chronic cerebral hypoperfusion. At repeated time points after 3-vessel occlusion (3-VO), animals were treated with 1 × 10(6) DiI-labeled (a) ex vivo-expanded embryonic-EPC (e-EPC), (b) cyclic AMP-differentiated embryonic-endothelial progenitor-derived cells (e-EPDC as biologic control) or, (c) saline. The cerebrovascular reserve capacity (CVRC) was assessed immediately before and on days 7 and 21 after 3-VO. Structural effects were assessed by latex perfusion, immunohistochemistry, and intravital fluorescence video microscopy on day 21. Three-vessel occlusion resulted in a significant impairment of the CVRC with better functional recovery after treatment with e-EPC (16.4±8%) compared with e-EPDC (3.7±8%) or saline (6.4±9%) by day 21 (P<0.05), which was paralleled by a significant increase in the vessel diameters of the anterior Circle of Willis, a significantly higher number of leptomeningeal anastomoses and higher parenchymal capillary density in e-EPC-treated animals. Interestingly, despite in vivo interaction of e-EPC with the cerebral endothelium, e-EPC incorporation into the cerebral vasculature was not observed. Our results suggest that EPC may serve as a novel therapeutic agent in clinical trials for nonsurgical treatment of chronic cerebral hemodynamic impairment.

SUBMITTER: Hecht N

PROVIDER: S-EPMC4126089 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other

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Project description:Background:As discovered in our previous study, autologous endothelial progenitor cells (EPCs) protect against acute focal ischemia rat via the promotion of angiogenesis. However, it is unknown whether the EPCs that reached the deficient region were transplanted ones or the products of other auto-conversion cells they had promoted. This study aimed to gather direct evidence for determining if exogenous transplanted EPCs directly participate in angiogenesis in ischemic areas and attempted to clarify the related mechanism. Methods:First, EPCs were extracted in vitro from male rats, which were characterized by uptake of fluorescently labeled acetylated low-density lipoprotein (ac-LDL) intake and Ulex europaeus agglutinin (UEA-1) and subsequently introduced to middle cerebral artery occlusion (MCAO) female rats for 7 days after ischemia surgery. The EPC-treated animals received approximately 1×106 cells, while the control animals received phosphate buffered saline (PBS). The animals behavior function recovery were by a rotarod (TOR) test, while infarct volume was assessed by brain magnetic resonance imaging (MRI). CD31 antibody was used to determine the presence of EPCs in the ischemic zone, and sex-determining region Y (SRY) gene in-situ hybridization (ISH) traced the EPC process. In addition, immunohistochemistry and Western blot were used to assess B-cell lymphoma 2 (Bcl-2) expression in the ischemic brain. Results:Behavior tests and MRI of all ischemic stroke groups on postoperative day 14 indicated that EPCs were more effective in behavior function recovery and reducing infarct volume and gliosis status than the control group. Cluster of differentiation (CD31) immunofluorescent staining and SRY gene ISH demonstrated that EPCs yielded a better outcome in both angiogenesis and exogenous cell homing status. We also observed increased Bcl-2 distribution and higher plasma Bcl-2 levels in the EPC-treated group compared to the control group. Conclusions:Our results provide direct evidence that exogenous EPCs can participate in angiogenesis to improve neurological outcome and revascularization directly after stroke, with Bcl-2 playing an important role in this process.

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Endothelial progenitor cells augment collateralization and hemodynamic rescue in a model of chronic cerebral ischemia.

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