GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression

Jin Liu, Lihong Pan, Wenxuan Hong, Siqin Chen, Peiyuan Bai, Wei Luo, Xiaolei Sun, Furong He, Xinlin Jia, Jialiang Cai, Yingjie Chen, Kai Hu, Zhenju Song (), Junbo Ge and Aijun Sun ()
Additional contact information
Jin Liu: Fudan University
Lihong Pan: National Health Commission
Wenxuan Hong: Fudan University
Siqin Chen: National Health Commission
Peiyuan Bai: Fudan University
Wei Luo: Fudan University
Xiaolei Sun: Fudan University
Furong He: Xiang’an Hospital of Xiamen University
Xinlin Jia: Shanghai Jiao Tong University School of Medicine
Jialiang Cai: Fudan University
Yingjie Chen: University of Mississippi Medical Center 2500N. State St
Kai Hu: Fudan University
Zhenju Song: Fudan University
Junbo Ge: Fudan University
Aijun Sun: Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Regulatory T cells (Tregs) are critically involved in neovascularization, an important compensatory mechanism in peripheral artery disease. The contribution of G protein coupled receptor 174 (GPR174), which is a regulator of Treg function and development, in neovascularization remains elusive. Here, we show that genetic deletion of GPR174 in Tregs potentiated blood flow recovery in mice after hindlimb ischemia. GPR174 deficiency upregulates amphiregulin (AREG) expression in Tregs, thereby enhancing endothelial cell functions and reducing pro-inflammatory macrophage polarization and endothelial cell apoptosis. Mechanically, GPR174 regulates AREG expression by inhibiting the nuclear accumulation of early growth response protein 1 (EGR1) via Gαs/cAMP/PKA signal pathway activation. Collectively, these findings demonstrate that GPR174 negatively regulates angiogenesis and vascular remodeling in response to ischemic injury and that GPR174 may be a potential molecular target for therapeutic interventions of ischemic vascular diseases.

Date: 2022
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DOI: 10.1038/s41467-022-35159-8

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