title: Vascular endothelial growth factor stimulates endothelial differentiation from mesenchymal stem cells via Rho/myocardin-related transcription factor--a signaling pathway.
abstract: Mesenchymal stem cells (MSCs) are pluripotent progenitors that can differentiate into a variety of cell types. Vascular endothelial growth factor (VEGF) is one of the major factors of initiating and regulating angiogenesis. It has been reported that VEGF can induce MSCs differentiated into endothelial cells (ECs). However, the mechanism that VEGF-induced MSC differentiation is not completely understood. Here, we showed that VEGF induced human and rat bone marrow-derived MSCs differentiation to ECs. Rho family plays an important role in VEGF-induced endothelial cell migration and angiogenesis. Our results indicated that in MSCs, VEGF activated Rho/ROCK signaling pathway and promoted nuclear translocation of myocardin-related transcription factor-A (MRTF-A), which is controlled by Rho/ROCK signaling. In addition, Rho inhibitor C3 transferase, ROCK inhibitor Y27632 or depletion of endogenous MRTF-A abolished the VEGF-induced differentiation of MSCs into ECs. Furthermore, VEGF also enhanced the expression levels of CYR61/CCN1, as a regulator of vascular development and angiogenesis, and knockdown of endogenous MRTF-A reduced VEGF-induced the upregulation of CYR61/CCN1. Report assays with site-direct mutation analysis of CYR61/CCN1 promoter demonstrated that MRTF-A transactivated CYR61/CCN1 promoter mainly depending on CArG box. In this study, we identify the Rho/MRTF-A signaling pathway as a main actor in controlling VEGF-induced differentiation of human and rat bone marrow-derived MSCs into endothelial cells.
authors.affiliation: Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Shui-Jing
authors.initials: SJ
authors.lastname: Wang
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Zhang
authors.forename: Li-Bin
authors.initials: LB
authors.lastname: Mao
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Zhuang
authors.forename: Yan-Yang
authors.initials: YY
authors.lastname: Tang
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Luo
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Tong-Cun
authors.initials: TC
authors.lastname: Zhang
mesh_terms: D036002:ADP Ribose Transferases; D000577:Amides; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001905:Botulinum Toxins; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000096:biosynthesis / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011725:Pyridines; D051381:Rats; D017207:Rats, Sprague-Dawley; D012261:Ribonucleoproteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000577:Amides; C501849:CCN1 protein, rat; D018797:Cell Cycle Proteins; D055515:Cysteine-Rich Protein 61; D004791:Enzyme Inhibitors; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C121363:Hnrnpab protein, rat; D011725:Pyridines; D012261:Ribonucleoproteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C557977:myocardin-related transcription factor-A, rat; C467498:vascular endothelial growth factor A, rat; C108830:Y 27632; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D054460:rho-Associated Kinases; D001905:Botulinum Toxins