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; Aijun Sun

doi:10.1038/s41467-022-35159-8

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

Nat Commun. 2022 Dec 6;13(1):7519. doi: 10.1038/s41467-022-35159-8.

Authors

Jin Liu^#^{1

2

3

4}, Lihong Pan^#^{3

4

5}, Wenxuan Hong^#^{1

3

4}, Siqin Chen^#^{3

4

5}, Peiyuan Bai^{1

3

4}, Wei Luo^{1

3

4}, Xiaolei Sun^{1

3

4}, Furong He⁶, Xinlin Jia⁷, Jialiang Cai⁸, Yingjie Chen⁹, Kai Hu¹, Zhenju Song¹⁰, Junbo Ge^{1

3

4

5}, Aijun Sun^{11

12

13

14

15}

Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
² Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai, 201203, China.
³ Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China.
⁴ Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China.
⁵ Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
⁶ Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361000, China.
⁷ Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China.
⁸ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
⁹ Department of Physiology and Biophysics, University of Mississippi Medical Center 2500N. State St, Jackson, MS, 39216-4505, USA.
¹⁰ Department of Emergency Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. song.zhenju@zs-hospital.sh.cn.
¹¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. sun.aijun@zs-hospital.sh.cn.
¹² Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai, 201203, China. sun.aijun@zs-hospital.sh.cn.
¹³ Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China. sun.aijun@zs-hospital.sh.cn.
¹⁴ Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China. sun.aijun@zs-hospital.sh.cn.
¹⁵ Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. sun.aijun@zs-hospital.sh.cn.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Gene Deletion
Ischemia* / genetics
Mice
Receptors, G-Protein-Coupled* / genetics

Substances

GPR174 protein, mouse
Receptors, G-Protein-Coupled