Volume 43 Issue 1
Jan.  2022
Turn off MathJax
Article Contents
Lin Zhang, Shan-Shan Zhang, Kai-Fang Wang, Yi-Hui Li, Hui-Juan Xu, Kuan-Xiang Sun, Shi Ma, Hong-Mei Leng, Si-Zhu Chen, Wen-Jing Jia, Xian-Jun Zhu, Jie Li. Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice. Zoological Research, 2022, 43(1): 64-74. doi: 10.24272/j.issn.2095-8137.2021.281
Citation: Lin Zhang, Shan-Shan Zhang, Kai-Fang Wang, Yi-Hui Li, Hui-Juan Xu, Kuan-Xiang Sun, Shi Ma, Hong-Mei Leng, Si-Zhu Chen, Wen-Jing Jia, Xian-Jun Zhu, Jie Li. Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice. Zoological Research, 2022, 43(1): 64-74. doi: 10.24272/j.issn.2095-8137.2021.281

Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice

doi: 10.24272/j.issn.2095-8137.2021.281
#Authors contributed equally to this work
Funds:  This study was supported by the National Natural Science Foundation of China (82071009, 81700841) and by the Grant from Chinese Academy of Medical Sciences (2019-I2M-5-032)
More Information
  • Corresponding author: E-mail: doctorjacklee@163.com
  • Received Date: 2021-10-16
  • Accepted Date: 2021-11-29
  • Available Online: 2021-11-29
  • Publish Date: 2022-01-18
  • Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelial-mesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model (Tg-Twist1iEC+). Whole-mount retinas from Tg-Twist1iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/β-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a ‘valve’ in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV.
  • #Authors contributed equally to this work
  • loading
  • [1]
    Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH. 2009. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell, 137(6): 1124-1135.
    Campochiaro PA. 2015. Molecular pathogenesis of retinal and choroidal vascular diseases. Progress in retinal and eye research, 49: 67-81.
    Capitão M & Soares R. 2016. Angiogenesis and Inflammation Crosstalk in Diabetic Retinopathy. Journal of cellular biochemistry, 117(11): 2443-2453.
    Chan-Ling T, Gole GA, Quinn GE, Adamson SJ, Darlow BA. 2018. Pathophysiology, screening and treatment of ROP: A multi-disciplinary perspective. Progress in retinal and eye research, 62: 77-119.
    Chen HF, Huang CH, Liu CJ, Hung JJ, Hsu CC, Teng SC, Wu KJ. 2014. Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis. Nature communications, 5: 4697.
    Chen HF & Wu KJ. 2016. Endothelial Transdifferentiation of Tumor Cells Triggered by the Twist1-Jagged1-KLF4 Axis: Relationship between Cancer Stemness and Angiogenesis. Stem cells international, 2016: 6439864.
    Cheung N, Mitchell P, Wong TY. 2010. Diabetic retinopathy. Lancet (London, England), 376(9735): 124-136.
    Claxton S, Kostourou V, Jadeja S, Chambon P, Hodivala-Dilke K, Fruttiger M. 2008. Efficient, inducible Cre-recombinase activation in vascular endothelium. Genesis (New York, N. Y. : 2000), 46(2): 74-80.
    Coxam B, Sabine A, Bower NI, Smith KA, Pichol-Thievend C, Skoczylas R, Astin JW, Frampton E, Jaquet M, Crosier PS, Parton RG, Harvey NL, Petrova TV, Schulte-Merker S, Francois M, Hogan BM. 2014. Pkd1 regulates lymphatic vascular morphogenesis during development. Cell reports, 7(3): 623-633.
    Hartnett ME & Penn JS. 2012. Mechanisms and management of retinopathy of prematurity. The New England journal of medicine, 367(26): 2515-2526.
    Kaushik K & Das A. 2020. TWIST1-Reprogrammed Endothelial Cell Transplantation Potentiates Neovascularization-Mediated Diabetic Wound Tissue Regeneration. Diabetes, 69(6): 1232-1247.
    Kim J, Kim YH, Kim J, Park DY, Bae H, Lee DH, Kim KH, Hong SP, Jang SP, Kubota Y, Kwon YG, Lim DS, Koh GY. 2017. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. The Journal of clinical investigation, 127(9): 3441-3461.
    Kim YH, Choi J, Yang MJ, Hong SP, Lee CK, Kubota Y, Lim DS, Koh GY. 2019. A MST1-FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis. Nature communications, 10(1): 838.
    Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA, Yanagisawa M. 2001. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Developmental biology, 230(2): 230-242.
    Koo YJ, Kim TJ, Min KJ, So KA, Jung US, Hong JH. 2017. CXCL11 mediates TWIST1-induced angiogenesis in epithelial ovarian cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 39(5): 1010428317706226.
    Krohne TU, Müller A, Larsen PP, Holz FG. 2018. [Long-term effects of anti-VEGF therapy for retinopathy of prematurity]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft, 115(6): 464-468.
    Lee SY, Surbeck JW, Drake M, Saunders A, Jin HD, Shah VA, Rajala RV. 2020. Increased Glial Fibrillary Acid Protein and Vimentin in Vitreous Fluid as a Biomarker for Proliferative Vitreoretinopathy. Investigative ophthalmology & visual science, 61(5): 22.
    Li J, Liu CH, Sun Y, Gong Y, Fu Z, Evans LP, Tian KT, Juan AM, Hurst CG, Mammoto A, Chen J. 2014. Endothelial TWIST1 promotes pathological ocular angiogenesis. Investigative ophthalmology & visual science, 55(12): 8267-8277.
    Li K, Zhang J, Tian Y, He Y, Xu X, Pan W, Gao Y, Chen F, Wei L. 2020. The Wnt/β-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer. Oncogene, 39(11): 2258-2274.
    Liu Z, Yan S, Wang J, Xu Y, Wang Y, Zhang S, Xu X, Yang Q, Zeng X, Zhou Y, Gu X, Lu S, Fu Z, Fulton DJ, Weintraub NL, Caldwell RB, Zhang W, Wu C, Liu XL, Chen JF, Ahmad A, Kaddour-Djebbar I, Al-Shabrawey M, Li Q, Jiang X, Sun Y, Sodhi A, Smith L, Hong M, Huo Y. 2017. Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis. Nature communications, 8(1): 584.
    Low-Marchelli JM, Ardi VC, Vizcarra EA, Van Rooijen N, Quigley JP, Yang J. 2013. Twist1 induces CCL2 and recruits macrophages to promote angiogenesis. Cancer research, 73(2): 662-671.
    Mammoto T, Jiang E, Jiang A, Lu Y, Juan AM, Chen J, Mammoto A. 2013. Twist1 controls lung vascular permeability and endotoxin-induced pulmonary edema by altering Tie2 expression. PloS one, 8(9): e73407.
    Mitchell P, Liew G, Gopinath B, Wong TY. 2018. Age-related macular degeneration. Lancet (London, England), 392(10153): 1147-1159.
    Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, He J, Shen W, Meng X, Jin X, Gong Z. 2020. lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling. Molecular cancer, 19(1): 9.
    Park JA & Kwon YG. 2018. Hippo-YAP/TAZ signaling in angiogenesis. BMB reports, 51(3): 157-162.
    Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. 2008. Vascular endothelial growth factor in eye disease. Progress in retinal and eye research, 27(4): 331-371.
    Pitulescu ME, Schmidt I, Benedito R, Adams RH. 2010. Inducible gene targeting in the neonatal vasculature and analysis of retinal angiogenesis in mice. Nature protocols, 5(9): 1518-1534.
    Potente M & Carmeliet P. 2017. The Link Between Angiogenesis and Endothelial Metabolism. Annual review of physiology, 79: 43-66.
    Rodrigues CO, Nerlick ST, White EL, Cleveland JL, King ML. 2008. A Myc-Slug (Snail2)/Twist regulatory circuit directs vascular development. Development (Cambridge, England), 135(11): 1903-1911.
    Schmidt JM, Panzilius E, Bartsch HS, Irmler M, Beckers J, Kari V, Linnemann JR, Dragoi D, Hirschi B, Kloos UJ, Sass S, Theis F, Kahlert S, Johnsen SA, Sotlar K, Scheel CH. 2015. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell reports, 10(2): 131-139.
    Selvam S, Kumar T, Fruttiger M. 2018. Retinal vasculature development in health and disease. Progress in retinal and eye research, 63: 1-19.
    Smith LE, Wesolowski E, Mclellan A, Kostyk SK, D'amato R, Sullivan R, D'amore PA. 1994. Oxygen-induced retinopathy in the mouse. Investigative ophthalmology & visual science, 35(1): 101-111.
    Sossey-Alaoui K, Pluskota E, Davuluri G, Bialkowska K, Das M, Szpak D, Lindner DJ, Downs-Kelly E, Thompson CL, Plow EF. 2014. Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 28(5): 2260-2271.
    Sun KX, Jiang XY, Li X, Su YJ, Wang JL, Zhang L, Yang YM, Zhu XJ. 2021. Deletion of phosphatidylserine flippase β-subunit Tmem30a in satellite cells leads to delayed skeletal muscle regeneration. Zoological research, 42(5): 650-659.
    Thisse B, El Messal M, Perrin-Schmitt F. 1987. The twist gene: isolation of a Drosophila zygotic gene necessary for the establishment of dorsoventral pattern. Nucleic acids research, 15(8): 3439-3453.
    Tseng JC, Chen HF, Wu KJ. 2015. A twist tale of cancer metastasis and tumor angiogenesis. Histology and histopathology, 30(11): 1283-1294.
    Usui-Ouchi A & Friedlander M. 2019. Anti-VEGF therapy: higher potency and long-lasting antagonism are not necessarily better. The Journal of clinical investigation, 129(8): 3032-3034.
    Villacampa P, Menger KE, Abelleira L, Ribeiro J, Duran Y, Smith AJ, Ali RR, Luhmann UF, Bainbridge JWB. 2017. Accelerated oxygen-induced retinopathy is a reliable model of ischemia-induced retinal neovascularization. PloS one, 12(6): e0179759.
    Wang LT, Chiou SS, Chai CY, Hsi E, Chiang CM, Huang SK, Wang SN, Yokoyama KK, Hsu SH. 2017. Transcription factor SPZ1 promotes TWIST-mediated epithelial-mesenchymal transition and oncogenesis in human liver cancer. Oncogene, 36(31): 4405-4414.
    Wong TY, Cheung CM, Larsen M, Sharma S, Simó R. 2016. Diabetic retinopathy. Nature reviews. Disease primers, 2: 16012.
    Yang DH, Yoon JY, Lee SH, Bryja V, Andersson ER, Arenas E, Kwon YG, Choi KY. 2009. Wnt5a is required for endothelial differentiation of embryonic stem cells and vascularization via pathways involving both Wnt/beta-catenin and protein kinase Calpha. Circulation research, 104(3): 372-379.
    Yang F, Guo Z, He C, Qing L, Wang H, Wu J, Lu X. 2021. Cancer-associated fibroblasts promote cell proliferation and invasion via paracrine Wnt/IL1β signaling pathway in human bladder cancer. Neoplasma, 68(1): 79-86.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. 2004. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117(7): 927-939.
    Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ. 2008. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nature cell biology, 10(3): 295-305.
    Yang WH, Lan HY, Huang CH, Tai SK, Tzeng CH, Kao SY, Wu KJ, Hung MC, Yang MH. 2012. RAC1 activation mediates Twist1-induced cancer cell migration. Nature cell biology, 14(4): 366-374.
    Ye X, Wang Y, Cahill H, Yu M, Badea TC, Smallwood PM, Peachey NS, Nathans J. 2009. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell, 139(2): 285-298.
    Zhang L, Zhang X, Xu H, Huang L, Zhang S, Liu W, Yang Y, Fei P, Li S, Yang M, Zhao P, Zhu X, Yang Z. 2020. Exome sequencing revealed Notch ligand JAG1 as a novel candidate gene for familial exudative vitreoretinopathy. Genetics in medicine : official journal of the American College of Medical Genetics, 22(1): 77-84.
    Zhang S, Liu W, Yang Y, Sun K, Li S, Xu H, Yang M, Zhang L, Zhu X. 2019. TMEM30A deficiency in endothelial cells impairs cell proliferation and angiogenesis. Journal of cell science, 132(7).
    Zhao Z, Rahman MA, Chen ZG, Shin DM. 2017. Multiple biological functions of Twist1 in various cancers. Oncotarget, 8(12): 20380-20393.
    Zhou Y, Wang Y, Tischfield M, Williams J, Smallwood PM, Rattner A, Taketo MM, Nathans J. 2014. Canonical WNT signaling components in vascular development and barrier formation. The Journal of clinical investigation, 124(9): 3825-3846.
    Zhu X, Yang M, Zhao P, Li S, Zhang L, Huang L, Huang Y, Fei P, Yang Y, Zhang S, Xu H, Yuan Y, Zhang X, Zhu X, Ma S, Hao F, Sundaresan P, Zhu W, Yang Z. 2021. Catenin α 1 mutations cause familial exudative vitreoretinopathy by overactivating Norrin/β-catenin signaling. The Journal of clinical investigation, 131(6).
  • ZR-2021-281 Supplementary Materials.pdf
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (693) PDF downloads(79) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint