VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway  

作　　者：Chunsik Lee Rongyuan Chen Guangli Sun Xialin Liu Xianchai Lin Chang He Liying Xing Lixian Liu Lasse DJensen Anil Kumar Harald FLanger Xiangrong Ren Jianing Zhang Lijuan Huang Xiangke Yin JongKyong Kim Juanhua Zhu Guanqun Huang Jiani Li Weiwei Lu Wei Chen Juanxi Liu Jiaxin Hu Qihang Sun Weisi Lu Lekun Fang Shasha Wang Haiqing Kuang Yihan Zhang Geng Tian Jia Mi Bi-Ang Kang Masashi Narazaki Aaron Prodeus Luc Schoonjans David MOrnitz Jean Gariepy Guy Eelen Mieke Dewerchin Yunlong Yang Jing-Song Ou Antonio Mora Jin Yao Chen Zhao Yizhi Liu Peter Carmeliet Yihai Cao Xuri Li 

机构地区：[1]State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University and Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,P.R.China [2]Affiliated Eye Hospital of Nanjing Medical University,Nanjing 210000,China [3]Department of Obstetrics and Gynecology,Guangdong Provincial Key Laboratory of Major Obstetric Diseases,Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology,The Third Affiliated Hospital of Guangzhou Medical University,Guangzhou,China [4]Shenzhen Eye Hospital,Jinan University,Shenzhen Eye Institute,Shenzhen,China [5]Department of Health,Medical and Caring Sciences,Division of Diagnostics and Specialist Medicine,Linköping University,58183 Linköping,Sweden [6]Department of Cardiology,Angiology,Haemostaseology and Medical Intensive Care,University Medical Centre Mannheim,Medical Faculty Mannheim,Heidelberg University,Mannheim,Germany [7]DZHK(German Research Centre for Cardiovascular Research),partner site Mannheim/Heidelberg,Mannheim,Germany [8]European Center for Angioscience,Medical Faculty Mannheim,Heidelberg University,Mannheim,Germany [9]Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease,Guangdong Research Institute of Gastroenterology,Department of Colorectal Surgery,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,China [10]Eye Institute,Eye and ENT Hospital,Shanghai Medical College,Fudan University,Key Laboratory of Myopia of State Health Ministry(Fudan University)and Shanghai Key Laboratory of Visual Impairment and Restoration,200031 Shanghai,China [11]Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment,Binzhou Medical University,Yantai 264003,P.R.China [12]Division of Cardiac Surgery,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases,NHC key Laboratory of Assisted Circulation(Sun Yat-sen University),The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,China [13]Depart

出　　处：《Signal Transduction and Targeted Therapy》2023年第9期4380-4393,共14页信号转导与靶向治疗（英文）

基　　金：This study is supported by the State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,and Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,P.R.China;the National Natural Science Foundation of China(82150710555 and 82220108016 to X.Li,81970823 to Jin Yao and 81830013 to J.O.);a Key Research and Development Plan of Shandong Province(2016GSF201100);the Fundamental Research Funds for the Central Universities(19ykpy151);the long-term structural Methusalem funding by the Flemish Government,Belgium;the Deutsche Forschungsge-meinschaft(Project No.:394046768-SFB1366);the DZHK partner site Mannheim/Heidelberg to H.F.L.,an ERA PerMed 2020 JTC grant“PROGRESS”.

摘　　要：Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases.It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms.Using comprehensive in vitro and in vivo methods and models,we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed.Mechanistically,we unveil that VEGF-B binds to FGFR1,induces FGFR1/VEGFR1 complex formation,and suppresses FGF2-induced Erk activation,and inhibits FGF2-driven angiogenesis and tumor growth.Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway.Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels,caution is warranted when modulating VEGF-B activity to treat neovascular diseases.

关 键 词：FGFR1 FGF2 drugs 

分 类 号：R543[医药卫生—心血管疾病]