Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Mol Med (Berl). 2021 Jul;99(7):993-1008. doi: 10.1007/s00109-021-02067-1. Epub 2021 Apr 6.
Angiogenesis is an integral process in many ischemic disorders, and vascular endothelial growth factor (VEGF) plays an important role in it. Protein arginine methyltransferase 4 (PRMT4), a member of the type I PRMT family, is involved in various biological activities, but its role in endothelial cell (EC) remains elusive. Here, we aimed to investigate the role of PRMT4 in ischemic angiogenesis and explore the possible underlying mechanism. We found that PRMT4 was upregulated in ischemic muscles, and VEGF treatment potentiated its expression in ECs. In vitro, adenovirus-mediated PRMT4 overexpression promoted, while its gene disruption inhibited, EC proliferation, migration, and tube formation. In an in vivo hindlimb ischemia model, forced expression of PRMT4 in ECs showed accelerated blood flow recovery and increased capillary density, whereas its knockdown exhibited the opposite effect. Mechanistically, PRMT4 activated the transcription of VEGF via the interaction with Y-box binding protein-1 (YB1), leading to accelerated angiogenesis. Interestingly, the loss of YB1 partially abolished PRMT4-mediated angiogenesis in vitro. Collectively, our data revealed that PRMT4 promoted angiogenesis through interacting with YB1 and the consequential VEGF upregulation, suggesting that PRMT4 may present as a potential therapeutic target in ischemic angiogenesis. KEY MESSAGES: •PRMT4 is induced by VEGF and upregulated in a hindlimb ischemia model. •PRMT4 promotes angiogenesis both in vitro and in vivo. •PRMT4 regulates VEGF expression through interacting with YB1. •YB1 knockdown retards PRMT4-mediated angiogenic effects in vitro.
血管生成是许多缺血性疾病的一个组成过程，血管内皮生长因子（VEGF）在其中起着重要作用。蛋白精氨酸甲基转移酶 4（PRMT4）是 I 型 PRMT 家族的成员，参与多种生物活性，但它在血管内皮细胞（EC）中的作用尚不清楚。在这里，我们旨在研究 PRMT4 在缺血性血管生成中的作用，并探讨其潜在的机制。我们发现 PRMT4 在缺血肌肉中上调，VEGF 处理增强了其在 EC 中的表达。在体外，腺病毒介导的 PRMT4 过表达促进了 EC 的增殖、迁移和管形成，而其基因缺失则抑制了这一过程。在体内后肢缺血模型中，EC 中 PRMT4 的强制表达显示出更快的血流恢复和增加的毛细血管密度，而其敲低则表现出相反的效果。在机制上，PRMT4 通过与 Y 盒结合蛋白 1（YB1）相互作用激活 VEGF 的转录，从而加速血管生成。有趣的是，YB1 的缺失部分消除了 PRMT4 在体外介导的血管生成。总之，我们的数据表明，PRMT4 通过与 YB1 相互作用和随后的 VEGF 上调促进血管生成，这表明 PRMT4 可能成为缺血性血管生成的潜在治疗靶点。
