Jun-Ming Tang1, Bin Luo2, Jun-hui Xiao3, Yan-xia Lv2, Xiao-lin Li3, Jin-he Zhao3, Fei Zheng3, Lei Zhang3, Long Chen3, Jian-Ye Yang3, Lin-Yun Guo3, Lu Wang3, Yu-Wen Yan3, Ya-Mo Pan3, Jia-Ning Wang3, Dong-sheng Li3, Yu Wan4, Shi-You Chen5. 1. Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Department of Physiology and Key Lab of human Embryonic Stem Cell of Hubei Province, Hubei University of Medicine, Hubei 442000, China; Center for Medical Research and Department of Physiology, School of Basic Medical Sciences, Wuhan University, Hubei 430071, China. Electronic address: tangjm416@163.com. 2. Department of Physiology and Key Lab of human Embryonic Stem Cell of Hubei Province, Hubei University of Medicine, Hubei 442000, China. 3. Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China. 4. Center for Medical Research and Department of Physiology, School of Basic Medical Sciences, Wuhan University, Hubei 430071, China. Electronic address: wanyu@whu.edu.cn. 5. Department of Physiology & Pharmacology, The University of Georgia, Athens, GA 30602, USA.
Abstract
BACKGROUND: The objective of this study was to determine whether vascular endothelial growth factor (VEGF)-A subtypes improve cardiac stem cell (CSC) engraftment and promote CSC-mediated myocardial repair in the infarcted heart. METHODS: CSCs were treated with VEGF receptor (VEGFR) inhibitors, VCAM-1 antibody (VCAM-1-Ab), or PKC-α inhibitor followed by the treatment with VEGF-A. CSC adhesion assays were performed in vitro. In vivo, the PKH26-labeled and VCAM-1-Ab or PKC-α inhibitor pre-treated CSCs were treated with VEGF-A followed by implantation into infarcted rat hearts. The hearts were then collected for measuring CSC engraftment and evaluating cardiac fibrosis and function 3 or 28days after the CSC transplantation. RESULTS: All three VEGF-A subtypes promoted CSC adhesion to extracellular matrix and endothelial cells. VEGF-A-mediated CSC adhesion required VEGFR and PKCα signaling. Importantly, VEGF-A induced VCAM-1, but not ICAM-1 expression in CSCs through PKCα signaling. In vivo, VEGF-A promoted the engraftment of CSCs in infarcted hearts, which was attenuated by PKCα inhibitor or VCAM-1-Ab. Moreover, VEGF-A-mediated CSC engraftment resulted in a reduction in infarct size and fibrosis. Functional studies showed that the transplantation of the VEGF-A-treated CSCs stimulated extensive angiomyogenesis in infarcted hearts as indicated by the expression of cardiac troponin T and von Willebrand factor, leading to an improved performance of left ventricle. Blockade of PKCα signaling or VCAM-1 significantly diminished the beneficial effects of CSCs treated with VEGF-A. CONCLUSION: VEGF-A promotes myocardial repair through, at least in part, enhancing the engraftment of CSCs mediated by PKCα/VCAM-1 pathway.
BACKGROUND: The objective of this study was to determine whether vascular endothelial growth factor (VEGF)-A subtypes improve cardiac stem cell (CSC) engraftment and promote CSC-mediated myocardial repair in the infarcted heart. METHODS: CSCs were treated with VEGF receptor (VEGFR) inhibitors, VCAM-1 antibody (VCAM-1-Ab), or PKC-α inhibitor followed by the treatment with VEGF-A. CSC adhesion assays were performed in vitro. In vivo, the PKH26-labeled and VCAM-1-Ab or PKC-α inhibitor pre-treated CSCs were treated with VEGF-A followed by implantation into infarctedrat hearts. The hearts were then collected for measuring CSC engraftment and evaluating cardiac fibrosis and function 3 or 28days after the CSC transplantation. RESULTS: All three VEGF-A subtypes promoted CSC adhesion to extracellular matrix and endothelial cells. VEGF-A-mediated CSC adhesion required VEGFR and PKCα signaling. Importantly, VEGF-A induced VCAM-1, but not ICAM-1 expression in CSCs through PKCα signaling. In vivo, VEGF-A promoted the engraftment of CSCs in infarcted hearts, which was attenuated by PKCα inhibitor or VCAM-1-Ab. Moreover, VEGF-A-mediated CSC engraftment resulted in a reduction in infarct size and fibrosis. Functional studies showed that the transplantation of the VEGF-A-treated CSCs stimulated extensive angiomyogenesis in infarcted hearts as indicated by the expression of cardiac troponin T and von Willebrand factor, leading to an improved performance of left ventricle. Blockade of PKCα signaling or VCAM-1 significantly diminished the beneficial effects of CSCs treated with VEGF-A. CONCLUSION:VEGF-A promotes myocardial repair through, at least in part, enhancing the engraftment of CSCs mediated by PKCα/VCAM-1 pathway.
Authors: K Dergilev; Z Tsokolaeva; P Makarevich; I Beloglazova; E Zubkova; M Boldyreva; E Ratner; D Dyikanov; M Menshikov; A Ovchinnikov; F Ageev; Ye Parfyonova Journal: Biomed Res Int Date: 2018-06-25 Impact factor: 3.411