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 D. Jensen, Anil Kumar, Harald F. Langer, Xiangrong Ren, Jianing Zhang, Lijuan Huang, Xiangke Yin, J. 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 Gariépy, Guy Eelen, Mieke Dewerchin, Yunlong Yang, Jing‐Song Ou, Antonio Mora, Jin Yao, Chen Zhao, Yizhi Liu, Peter Carmeliet, Yihai Cao, Xuri Li
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.