尽管VEGF-B早在很久以前即被发现为VEGF-A的同源物，但VEGF-B的血管生成效应仍然不甚清楚，不同研究组得出了有限且多样的结果。然而，目前正在使用抑制VEGF-B及其他VEGF家族成员的药物来治疗不同新生血管性疾病的患者。因此，更好地了解VEGF-B的血管生成效应及其潜在机制至关重要。通过全面的体外和体内方法和模型，我们首次发现了VEGF-B作为内源性血管生成抑制剂的意想不到和令人惊讶的功能，当后者丰富表达时，它可以通过抑制FGF2/FGFR1信号通路发挥作用。在机制上，我们揭示了VEGF-B与FGFR1结合，诱导FGFR1/VEGFR1复合物形成，并抑制FGF2诱导的Erk活化，从而抑制FGF2驱动的血管生成和肿瘤生长。我们的工作揭示了VEGF-B在捆绑FGF2/FGFR1途径方面的新功能，这是以前未被认识到的。鉴于VEGF-B在高FGF2/FGFR1水平条件下的抗血管生成特性，当调节VEGF-B活性以治疗新生血管性疾病时需要谨慎。©2023年，四川大学华西医院。

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.