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

Chunsik Lee; Rongyuan Chen; Guangli Sun; Xialin Liu; Xianchai Lin; Chang He; Liying Xing; Lixian Liu; Lasse Dahl Ejby Jensen; Anil Kumar; Harald F. Langer; 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 M. Ornitz; Jean Gariepy; Guy Eelen; Mieke A. Dewerchin; Yunlong Yang; Jingsong Ou; Antonio Mora; Jin Yao; Chen Zhao; Yizhi Liu; Peter F.M. Carmeliet; Yihai Cao; Xuri Li

doi:10.1038/s41392-023-01539-9

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

Chunsik Lee, Rongyuan Chen, Guangli Sun, Xialin Liu, Xianchai Lin, Chang He, Liying Xing, Lixian Liu, Lasse Dahl Ejby Jensen, Anil Kumar, Harald F. Langer, Xiangrong Ren, Jianing Zhang, Lijuan Huang, Xiangke Yin, Jongkyong Kim, Juanhua Zhu, Guanqun Huang, Jiani Li, Weiwei LuWei 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 M. Ornitz, Jean Gariepy, Guy Eelen, Mieke A. Dewerchin, Yunlong Yang, Jingsong Ou, Antonio Mora, Jin Yao, Chen Zhao, Yizhi Liu, Peter F.M. Carmeliet, Yihai Cao, Xuri Li

Biological Sciences

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

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. © 2023, West China Hospital, Sichuan University.

Original language	American English
Journal	Signal Transduction and Targeted Therapy
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41392-023-01539-9
State	Published - 2023

Keywords

fibroblast growth factor 2
fibroblast growth factor receptor 1
vasculotropin
FGFR1 protein
human
vasculotropin B
angiogenesis
animal cell
animal experiment
animal model
Article
cell culture
cell migration
chemoluminescence
enzyme linked immunosorbent assay
high performance liquid chromatography
human cell
immunofluorescence
immunoprecipitation
immunoreactivity
mass spectrometry
mouse
neovascular glaucoma
nonhuman
phosphorylation
protein determination
tumor growth
umbilical vein endothelial cell
Western blotting
genetics
immunotherapy
Fibroblast Growth Factor 2
Humans
Immunotherapy
Receptor
Fibroblast Growth Factor
Type 1
Vascular Endothelial Growth Factor B

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10.1038/s41392-023-01539-9

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85168258801&doi=10.1038%2fs41392-023-01539-9&partnerID=40&md5=cfb5577f4bf202ddd22c4123349b5669

Cite this

Lee, C., Chen, R., Sun, G., Liu, X., Lin, X., He, C., Xing, L., Liu, L., Jensen, L. D. E., Kumar, A., Langer, H. F., Ren, X., Zhang, J., Huang, L., Yin, X., Kim, J., Zhu, J., Huang, G., Li, J., ... Li, X. (2023). VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway. Signal Transduction and Targeted Therapy, 8(1). https://doi.org/10.1038/s41392-023-01539-9

@article{6b804731ed6140b0b78985477df13047,

title = "VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway",

abstract = "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. {\textcopyright} 2023, West China Hospital, Sichuan University.",

keywords = "fibroblast growth factor 2, fibroblast growth factor receptor 1, vasculotropin, FGFR1 protein, human, vasculotropin B, angiogenesis, animal cell, animal experiment, animal model, Article, cell culture, cell migration, chemoluminescence, enzyme linked immunosorbent assay, high performance liquid chromatography, human cell, immunofluorescence, immunoprecipitation, immunoreactivity, mass spectrometry, mouse, neovascular glaucoma, nonhuman, phosphorylation, protein determination, tumor growth, umbilical vein endothelial cell, Western blotting, genetics, immunotherapy, Fibroblast Growth Factor 2, Humans, Immunotherapy, Receptor, Fibroblast Growth Factor, Type 1, Vascular Endothelial Growth Factor B",

author = "Chunsik Lee and Rongyuan Chen and Guangli Sun and Xialin Liu and Xianchai Lin and Chang He and Liying Xing and Lixian Liu and Jensen, {Lasse Dahl Ejby} and Anil Kumar and Langer, {Harald F.} and Xiangrong Ren and Jianing Zhang and Lijuan Huang and Xiangke Yin and Jongkyong Kim and Juanhua Zhu and Guanqun Huang and Jiani Li and Weiwei Lu and Wei Chen and Juanxi Liu and Jiaxin Hu and Qihang Sun and Weisi Lu and Lekun Fang and Shasha Wang and Haiqing Kuang and Yihan Zhang and Geng Tian and Jia Mi and Kang, {Bi Ang} and Masashi Narazaki and Aaron Prodeus and Luc Schoonjans and Ornitz, {David M.} and Jean Gariepy and Guy Eelen and Dewerchin, {Mieke A.} and Yunlong Yang and Jingsong Ou and Antonio Mora and Jin Yao and Chen Zhao and Yizhi Liu and Carmeliet, {Peter F.M.} and Yihai Cao and Xuri Li",

note = "cited By 3",

year = "2023",

doi = "10.1038/s41392-023-01539-9",

language = "American English",

volume = "8",

journal = "Signal Transduction and Targeted Therapy",

issn = "2095-9907",

publisher = "Springer Nature",

number = "1",

}

Lee, C, Chen, R, Sun, G, Liu, X, Lin, X, He, C, Xing, L, Liu, L, Jensen, LDE, Kumar, A, Langer, HF, Ren, X, Zhang, J, Huang, L, Yin, X, Kim, J, Zhu, J, Huang, G, Li, J, Lu, W, Chen, W, Liu, J, Hu, J, Sun, Q, Lu, W, Fang, L, Wang, S, Kuang, H, Zhang, Y, Tian, G, Mi, J, Kang, BA, Narazaki, M, Prodeus, A, Schoonjans, L, Ornitz, DM, Gariepy, J, Eelen, G, Dewerchin, MA, Yang, Y, Ou, J, Mora, A, Yao, J, Zhao, C, Liu, Y, Carmeliet, PFM, Cao, Y & Li, X 2023, 'VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway', Signal Transduction and Targeted Therapy, vol. 8, no. 1. https://doi.org/10.1038/s41392-023-01539-9

TY - JOUR

T1 - VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway

AU - Lee, Chunsik

AU - Chen, Rongyuan

AU - Sun, Guangli

AU - Liu, Xialin

AU - Lin, Xianchai

AU - He, Chang

AU - Xing, Liying

AU - Liu, Lixian

AU - Jensen, Lasse Dahl Ejby

AU - Kumar, Anil

AU - Langer, Harald F.

AU - Ren, Xiangrong

AU - Zhang, Jianing

AU - Huang, Lijuan

AU - Yin, Xiangke

AU - Kim, Jongkyong

AU - Zhu, Juanhua

AU - Huang, Guanqun

AU - Li, Jiani

AU - Lu, Weiwei

AU - Chen, Wei

AU - Liu, Juanxi

AU - Hu, Jiaxin

AU - Sun, Qihang

AU - Lu, Weisi

AU - Fang, Lekun

AU - Wang, Shasha

AU - Kuang, Haiqing

AU - Zhang, Yihan

AU - Tian, Geng

AU - Mi, Jia

AU - Kang, Bi Ang

AU - Narazaki, Masashi

AU - Prodeus, Aaron

AU - Schoonjans, Luc

AU - Ornitz, David M.

AU - Gariepy, Jean

AU - Eelen, Guy

AU - Dewerchin, Mieke A.

AU - Yang, Yunlong

AU - Ou, Jingsong

AU - Mora, Antonio

AU - Yao, Jin

AU - Zhao, Chen

AU - Liu, Yizhi

AU - Carmeliet, Peter F.M.

AU - Cao, Yihai

AU - Li, Xuri

N1 - cited By 3

PY - 2023

Y1 - 2023

N2 - 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. © 2023, West China Hospital, Sichuan University.

AB - 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. © 2023, West China Hospital, Sichuan University.

KW - fibroblast growth factor 2

KW - fibroblast growth factor receptor 1

KW - vasculotropin

KW - FGFR1 protein

KW - human

KW - vasculotropin B

KW - angiogenesis

KW - animal cell

KW - animal experiment

KW - animal model

KW - Article

KW - cell culture

KW - cell migration

KW - chemoluminescence

KW - enzyme linked immunosorbent assay

KW - high performance liquid chromatography

KW - human cell

KW - immunofluorescence

KW - immunoprecipitation

KW - immunoreactivity

KW - mass spectrometry

KW - mouse

KW - neovascular glaucoma

KW - nonhuman

KW - phosphorylation

KW - protein determination

KW - tumor growth

KW - umbilical vein endothelial cell

KW - Western blotting

KW - genetics

KW - immunotherapy

KW - Fibroblast Growth Factor 2

KW - Humans

KW - Immunotherapy

KW - Receptor

KW - Fibroblast Growth Factor

KW - Type 1

KW - Vascular Endothelial Growth Factor B

U2 - 10.1038/s41392-023-01539-9

DO - 10.1038/s41392-023-01539-9

M3 - Article

SN - 2095-9907

VL - 8

JO - Signal Transduction and Targeted Therapy

JF - Signal Transduction and Targeted Therapy

IS - 1

ER -

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

Abstract

Keywords

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