Li Huixian, He Chufeng, Zhu Ruiwen, Chen Francis M, Wang Lin, Leung Fung Ping, Tian Xiao Yu, Tse Gary, Wong Wing Tak
School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong 999077, China; State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong 999077, China.
School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong 999077, China; State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong 999077, China.
Cell Rep. 2023 Aug 29;42(8):112964. doi: 10.1016/j.celrep.2023.112964. Epub 2023 Aug 8.
Peripheral arterial disease (PAD) is one of the leading causes of cardiovascular morbidity and mortality worldwide, yet current trials on therapeutic angiogenesis remain suboptimal. Type 2 immunity is critical for post-ischemic regeneration, but its regulatory role in revascularization is poorly characterized. Here, we show that type 2 cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), are the key mediators in post-ischemic angiogenesis. IL-4/IL-13-deficient mice exhibit impaired reperfusion and muscle repair in an experimental model of PAD. We find that deletion of IL-4Rα in the endothelial compartment, rather than the myeloid compartment, leads to remarkable impairment in revascularization. Mechanistically, IL-4/IL-13 promote endothelial cell proliferation, migration, and tube formation via IL-4Rα/STAT6 signaling. Furthermore, attenuated IL-4/IL-13 expression is associated with the angiogenesis deficit in the setting of diabetic PAD, while IL-4/IL-13 treatment rescues this defective regeneration. Our findings reveal the therapeutic potential of type 2 cytokines in treating patients with muscle ischemia.
外周动脉疾病（PAD）是全球心血管疾病发病和死亡的主要原因之一，但目前关于治疗性血管生成的试验仍不尽人意。2型免疫对于缺血后再生至关重要，但其在血管再生中的调节作用尚不明确。在此，我们表明2型细胞因子白细胞介素-4（IL-4）和白细胞介素-13（IL-13）是缺血后血管生成的关键介质。在PAD实验模型中，IL-4/IL-13缺陷小鼠表现出再灌注和肌肉修复受损。我们发现，在内皮细胞而非髓样细胞中缺失IL-4Rα会导致血管再生显著受损。机制上，IL-4/IL-13通过IL-4Rα/STAT6信号通路促进内皮细胞增殖、迁移和管腔形成。此外，在糖尿病性PAD中，IL-4/IL-13表达减弱与血管生成缺陷有关，而IL-4/IL-13治疗可挽救这种有缺陷的再生。我们的研究结果揭示了2型细胞因子在治疗肌肉缺血患者中的治疗潜力。
