Involvement of endothelial progenitor cells in blood flow recovery through activation of the Wnt/β-catenin signaling pathway and inhibition of high oxidative stress in diabetic hindlimb ischemic rats

被引：4
作者：
Xu, Xiongfei [1 ,2 ]
Xie, Fei [3 ]
Wang, Yuping [4 ]
Zeng, Hong [1 ,2 ]
Shi, Sen [1 ,2 ]
Sun, Xiaolei [1 ,2 ]
He, Huqiang [1 ,2 ]
Zhang, Lei [1 ,2 ]
Wang, Weiming [1 ,2 ]
Xiang, Tao [5 ]
He, Yanzheng [1 ,2 ]
Liu, Yong [1 ,2 ]
机构：
[1] Southwest Med Univ, Dept Vasc Surg, Affiliated Hosp, Luzhou, Peoples R China
[2] Minist Educ, Collaborat Innovat Ctr Prevent & Treatment Cardio, Key Lab Med Electrophysiol, Luzhou, Peoples R China
[3] First Peoples Hosp Liangshan Yi Autonomous Prefec, Dept Thorac & Cardiovasc Surg, Xinchang, Peoples R China
[4] Southwest Med Univ, Dept Vasc Surg, Hosp Tradit Chinese Med, Luzhou, Peoples R China
[5] Southwest Med Univ, Affiliated Hosp, Dept Cardiovasc Med, Luzhou, Peoples R China
来源：
ADVANCES IN CLINICAL AND EXPERIMENTAL MEDICINE | 2022年 / 31卷 / 11期
关键词：
diabetic hindlimb ischemia; EPCs; Wnt/beta-catenin signaling pathway; oxidative stress; LIMB ISCHEMIA; ANGIOGENESIS; REVASCULARIZATION; DYSFUNCTION; ADHESION; ULCERS; EPCS; BONE;
D O I：
10.17219/acem/139094
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
Background. Diabetes mellitus (DM) often causes stenosis and occlusion of hindlimb blood vessels, which are also the main cause for hindlimb ischemia in elderly people. Objectives. To investigate the therapeutic effect of endothelial progenitor cell (EPC) transplantation on diabetic hindlimb ischemia. Materials and methods. Endothelial progenitor cells were separated, labeled with PKH-26 and transplanted into rat models (107 cells/100 g). Dichlorodihydrofluorescein diacetate (DCFH-DA) was used to detect any oxidative stress. Streptozotocin (STZ) was injected to establish a diabetic rat model and hindlimb ischemia model was established via operation. Western blotting was used to detect total beta-catenin (T-beta-catenin) and non-phospho- beta-catenin (NP-beta-catenin) levels. The malondialdehyde (MDA), superoxide dismutase (SOD), Wnt3a, Wnt5a and Wnt7a levels were detected using enzyme-linked immunosorbent assay (ELISA). Oxidative stress was measured using DCFH-DA and dihydroethidium (DHE). The endothelial biomarker CD31 was observed to highlight vessels, and PKH-26 to trace migration/adhesion of EPCs. Results. Endothelial progenitor cells were successfully isolated and identified, and diabetic hindlimb ischemic rat models were created. Tempol remarkably improved blood flow in diabetic hindlimb ischemic rats compared to DM+EPCs rats at 14days (p < 0.001) and 28 days post-operation (p < 0.001). Highoxidative stress wasobserved in diabetic hindlimb ischemic rats. Tempol significantly inhibited oxidative stress levels in diabetic hindlimb ischemic rats. Furthermore, Tempol significantly promoted angiogenesis in diabetic hindlimb ischemic rats compared to DM+EPCs rats. The beta-catenin inhibitor, XAV (DM+EPCs+Tempol+XAV group), significantly suppressed blood flow recovery and angiogenesis in diabetic hindlimb ischemic rats whencompared to the DM+EPCs+Tempol group at 14 days (p = 0.026) and 28 days (p < 0.001). The XAV remarkably reduced T-beta-catenin (p < 0.001) and N-beta-catenin (p = 0.030)levels in Tempol-treateddiabetic hindlimb ischemic rats, as comparedto the DM+EPCs+Tempol group. The Wnt5a participated in the pathology of diabetic hindlimb ischemia. Conclusions. There are high oxidative stress levels in both EPCs in high-glucose environments and diabetic hindlimb ischemia, which can lead to limited blood flow recovery. The high oxidative stress caused the inhibition of Wnt/beta-catenin signaling pathway, leading to limited blood flow recovery in diabetic hindlimb ischemia. At the same time, Wnt5a participated in the EPC-mediated blood flow recovery.
引用
收藏
页码：1215 / 1229
页数：15
相关论文
共 31 条
[1]   Isolation of putative progenitor endothelial cells for angiogenesis [J].
Asahara, T ;
Murohara, T ;
Sullivan, A ;
Silver, M ;
vanderZee, R ;
Li, T ;
Witzenbichler, B ;
Schatteman, G ;
Isner, JM .
SCIENCE, 1997, 275 (5302) :964-967
[2]   Human CD133+ Progenitor Cells Promote the Healing of Diabetic Ischemic Ulcers by Paracrine Stimulation of Angiogenesis and Activation of Wnt Signaling [J].
Barcelos, Luciola S. ;
Duplaa, Cecile ;
Kraenkel, Nicolle ;
Graiani, Gallia ;
Invernici, Gloria ;
Katare, Rajesh ;
Siragusa, Mauro ;
Meloni, Marco ;
Campesi, Ilaria ;
Monica, Manuela ;
Simm, Andreas ;
Campagnolo, Paola ;
Mangialardi, Giuseppe ;
Stevanato, Lara ;
Alessandri, Giulio ;
Emanueli, Costanza ;
Madeddu, Paolo .
CIRCULATION RESEARCH, 2009, 104 (09) :1095-U199
[3]   Accumulation of Phosphorylated β-Catenin Enhances ROS-Induced Cell Death in Presenilin-Deficient Cells [J].
Boo, Jung H. ;
Song, Hyundong ;
Kim, Ji E. ;
Kang, David E. ;
Mook-Jung, Inhee .
PLOS ONE, 2009, 4 (01)
[4]  
Chen YH, 2019, AM J TRANSL RES, V11, P1569
[5]   Activation of the Wnt Pathway Plays a Pathogenic Role in Diabetic Retinopathy in Humans and Animal Models [J].
Chen, Ying ;
Hu, Yang ;
Zhou, Ti ;
Zhou, Kevin K. ;
Mott, Robert ;
Wu, Mingyuan ;
Boulton, Michael ;
Lyons, Timothy J. ;
Gao, Guoquan ;
Ma, Jian-xing .
AMERICAN JOURNAL OF PATHOLOGY, 2009, 175 (06) :2676-2685
[6]   Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia [J].
Dai, Xiaozhen ;
Yan, Xiaoqing ;
Zeng, Jun ;
Chen, Jing ;
Wang, Yuehui ;
Chen, Jun ;
Li, Yan ;
Barati, Michelle T. ;
Wintergerst, Kupper A. ;
Pan, Kejian ;
Nystoriak, Matthew A. ;
Conklin, Daniel J. ;
Rokosh, Gregg ;
Epstein, Paul N. ;
Li, Xiaokun ;
Tan, Yi .
CIRCULATION RESEARCH, 2017, 120 (05) :E7-E23
[7]   Loss of histone deacetylase 2 inhibits oxidative stress induced by high glucose via the HO-1/SIRT1 pathway in endothelial progenitor cells [J].
Gao, Jie ;
Wang, Yuanhong ;
Li, Wei ;
Zhang, Jiayuan ;
Che, Yanling ;
Cui, Xuan ;
Sun, Boyu ;
Zhao, Gang .
GENE, 2018, 678 :1-7
[8]   Cultured endothelial cells display endogenous activation of the canonical Wnt signaling pathway and express multiple ligands, receptors, and secreted modulators of Wnt signaling [J].
Goodwin, Anne M. ;
Sullivan, Kaitlyn M. ;
D'Amore, Patricia A. .
DEVELOPMENTAL DYNAMICS, 2006, 235 (11) :3110-3120
[9]   Nitric oxide: a key factor behind the dysfunctionality of endothelial progenitor cells in diabetes mellitus type-2 [J].
Hamed, Saher ;
Brenner, Benjamin ;
Roguin, Ariel .
CARDIOVASCULAR RESEARCH, 2011, 91 (01) :9-15
[10]   Autologous bone marrow cell implantation as therapeutic angiogenesis for ischemic hindlimb in diabetic rat model [J].
Hirata, K ;
Li, TS ;
Nishida, M ;
Ito, H ;
Matsuzaki, M ;
Kasaoka, S ;
Hamano, K .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2003, 284 (01) :H66-H70
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