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

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.
Funding Agencies|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou P. R. China [510060]; National Natural Science Foundation of China [82150710555, 82220108016, 81970823, 81830013]; Key Research and Development Plan of Shandong Province [2016GSF201100]; Fundamental Research Funds for the Central Universities [19ykpy151]; long-term structural Methusalem; Flemish Government, Belgium; Deutsche Forschungsgemeinschaft [394046768 - SFB1366]; DZHK partner site Mannheim/Heidelberg; ERA PerMed 2020 JTC