VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Lee Chunsik, Chen Rongyuan, Sun Guangli, Liu Xialin, Lin Xianchai, He Chang, Xing Liying, Liu Lixian, Jensen Lasse D, Kumar Anil, Langer Harald F, Ren Xiangrong, Zhang Jianing, Huang Lijuan, Yin Xiangke, Kim JongKyong, Zhu Juanhua, Huang Guanqun, Li Jiani, Lu Weiwei, Chen Wei, Liu Juanxi, Hu Jiaxin, Sun Qihang, Lu Weisi, Fang Lekun, Wang Shasha, Kuang Haiqing, Zhang Yihan, Tian Geng, Mi Jia, Kang Bi-Ang, Narazaki Masashi, Prodeus Aaron, Schoonjans Luc, Ornitz David M, Gariepy Jean, Eelen Guy, Dewerchin Mieke, Yang Yunlong, Ou Jing-Song, Mora Antonio, Yao Jin, Zhao Chen, Liu Yizhi, Carmeliet Peter, Cao Yihai, Li Xuri
Аннотация
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.