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

  • 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;
  • And 28 more
Publication Date
Aug 18, 2023
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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. / status: published

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