Type 2 cytokines promote angiogenesis in ischemic muscle via endothelial IL-4Rα signaling
Huixian Li,
Chufeng He,
Ruiwen Zhu,
Francis M. Chen,
Lin Wang,
Fung Ping Leung,
Xiao Yu Tian,
Gary Tse,
Wing Tak Wong
Affiliations
Huixian Li
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; Corresponding author
Chufeng He
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
Ruiwen Zhu
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
Francis M. Chen
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
Lin Wang
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
Fung Ping Leung
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
Xiao Yu Tian
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
Gary Tse
School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong 999077, China; Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
Wing Tak Wong
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; Corresponding author
Summary: 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.
