IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 35; no. 12; pp. 2638 - 2646
• Main Authors: Yang, Tianshu, Lin, Qing, Zhao, Mengmeng, Hu, Yongguang, Yu, Ying, Jin, Jiayi, Zhou, Hongyan, Hu, Xiao, Wei, Rongbin, Zhang, Xuetao, Yang, Xiaoping, Liu, Gaoqin, Lu, Peirong, Xu, Guotong, Yang, Jianhua, Corry, David B, Su, Shao Bo, Liu, Shangfeng, Liu, Xialin
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.12.2015
• Subjects: Angiogenesis Inducing Agents - pharmacology; Animals; Animals, Newborn; Cell Hypoxia; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases - metabolism; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interleukin-1 - metabolism; Interleukin-1 - pharmacology; Interleukin-1 - toxicity; Mice, Inbred C57BL; Neovascularization, Physiologic - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Retinal Neovascularization - chemically induced; Retinal Neovascularization - metabolism; Retinal Neovascularization - pathology; Retinopathy of Prematurity - chemically induced; Retinopathy of Prematurity - metabolism; Retinopathy of Prematurity - pathology; RNA Interference; Time Factors; Transfection; cytokines; oxygen-induced retinopathy; inflammation; endothelial cell; interleukins
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.115.306543

OBJECTIVE—Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Interleukin 37 (IL-37) is a newly identified cytokine of the IL-1 family, some members of which are important in inflammation and angiogenesis. However, the function of IL-37 in angiogenesis remains unknown. We aimed to explore the regulatory role of IL-37 in pathological and physiological angiogenesis. APPROACH AND RESULTS—We found that IL-37 was expressed and secreted in endothelial cells and upregulated under hypoxic conditions. IL-37 enhanced endothelial cell proliferation, capillary formation, migration, and vessel sprouting from aortic rings with potency comparable with that of vascular endothelial growth factor. IL-37 activates survival signals including extracellular signal-regulated kinase 1/2 and AKT in endothelial cells. IL-37 promoted vessel growth in implanted Matrigel plug in vivo in a dose-dependent manner with potency comparable with that of basic fibroblast growth factor. In the mouse model of retinal vascular development, neonatal mice administrated with IL-37 displayed increased neovascularization. We demonstrated further that IL-37 promoted pathological angiogenesis in the mouse model of oxygen-induced retinopathy. CONCLUSIONS—Our findings suggest that IL-37 is a novel and potent proangiogenic cytokine with essential role in pathophy siological settings.