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

doi:10.1016/j.celrep.2023.112964

Type 2 cytokines promote angiogenesis in ischemic muscle via endothelial IL-4Rα signaling

Cell Rep. 2023 Aug 29;42(8):112964. doi: 10.1016/j.celrep.2023.112964. Epub 2023 Aug 8.

Authors

Huixian Li¹, Chufeng He², Ruiwen Zhu², Francis M Chen², Lin Wang², Fung Ping Leung², Xiao Yu Tian³, Gary Tse⁴, Wing Tak Wong⁵

Affiliations

¹ 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. Electronic address: lihuixian@link.cuhk.edu.hk.
² 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.
³ School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China.
⁴ 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.
⁵ 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. Electronic address: jack_wong@cuhk.edu.hk.

PMID: 37556326
DOI: 10.1016/j.celrep.2023.112964

Abstract

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.

Keywords: CP: Immunology; CP: Metabolism; IL-4Rα signaling; angiogenesis; ischemic muscle; peripheral arterial disease; type 2 cytokines.