Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
JCI Insight. 2022 May 9;7(9):e152481. doi: 10.1172/jci.insight.152481.
Arginine methylation mediated by protein arginine methyltransferases (PRMTs) has been shown to be an important posttranslational mechanism involved in various biological processes. Herein, we sought to investigate whether PRMT5, a major type II enzyme, is involved in pathological angiogenesis and, if so, to elucidate the molecular mechanism involved. Our results show that PRMT5 expression is significantly upregulated in ischemic tissues and hypoxic endothelial cells (ECs). Endothelial-specific Prmt5-KO mice were generated to define the role of PRMT5 in hindlimb ischemia-induced angiogenesis. We found that these mice exhibited impaired recovery of blood perfusion and motor function of the lower limbs, an impairment that was accompanied by decreased vascular density and increased necrosis as compared with their WT littermates. Furthermore, both pharmacological and genetic inhibition of PRMT5 significantly attenuated EC proliferation, migration, tube formation, and aortic ring sprouting. Mechanistically, we showed that inhibition of PRMT5 markedly attenuated hypoxia-induced factor 1-α (HIF-1α) protein stability and vascular endothelial growth factor-induced (VEGF-induced) signaling pathways in ECs. Our results provide compelling evidence demonstrating a crucial role of PRMT5 in hypoxia-induced angiogenesis and suggest that inhibition of PRMT5 may provide novel therapeutic strategies for the treatment of abnormal angiogenesis-related diseases, such as cancer and diabetic retinopathy.
精氨酸的甲基化由蛋白质精氨酸甲基转移酶（PRMTs）介导，已被证明是参与各种生物过程的重要翻译后机制。在此，我们试图研究主要的 II 型酶 PRMT5 是否参与病理性血管生成，如果是，阐明涉及的分子机制。我们的结果表明，PRMT5 表达在缺血组织和缺氧内皮细胞（ECs）中显著上调。生成内皮细胞特异性 Prmt5-KO 小鼠以确定 PRMT5 在缺血性后肢血管生成中的作用。我们发现，与 WT 同窝仔相比，这些小鼠的下肢血流灌注和运动功能恢复受损，血管密度降低，坏死增加。此外，PRMT5 的药理学和遗传学抑制均显著抑制 EC 的增殖、迁移、管状形成和主动脉环发芽。在机制上，我们表明 PRMT5 抑制显著减弱了缺氧诱导因子 1-α（HIF-1α）蛋白稳定性和血管内皮生长因子诱导（VEGF 诱导）的 EC 信号通路。我们的结果提供了令人信服的证据，证明 PRMT5 在缺氧诱导的血管生成中起关键作用，并表明抑制 PRMT5 可能为治疗异常血管生成相关疾病（如癌症和糖尿病性视网膜病变）提供新的治疗策略。
