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

Author

Listed:
  • Jin Liu

    (Fudan University
    Fudan University
    National Health Commission
    Chinese Academy of Medical Sciences)

  • Lihong Pan

    (National Health Commission
    Chinese Academy of Medical Sciences
    Fudan University)

  • Wenxuan Hong

    (Fudan University
    National Health Commission
    Chinese Academy of Medical Sciences)

  • Siqin Chen

    (National Health Commission
    Chinese Academy of Medical Sciences
    Fudan University)

  • Peiyuan Bai

    (Fudan University
    National Health Commission
    Chinese Academy of Medical Sciences)

  • Wei Luo

    (Fudan University
    National Health Commission
    Chinese Academy of Medical Sciences)

  • Xiaolei Sun

    (Fudan University
    National Health Commission
    Chinese Academy of Medical Sciences)

  • 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
    National Health Commission
    Chinese Academy of Medical Sciences
    Fudan University)

  • Aijun Sun

    (Fudan University
    Fudan University
    National Health Commission
    Chinese Academy of Medical Sciences)

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.

Suggested Citation

  • 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, 2022. "GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35159-8
    DOI: 10.1038/s41467-022-35159-8
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    References listed on IDEAS

    as
    1. Ruozhu Zhao & Xin Chen & Weiwei Ma & Jinyu Zhang & Jie Guo & Xiu Zhong & Jiacheng Yao & Jiahui Sun & Julian Rubinfien & Xuyu Zhou & Jianbin Wang & Hai Qi, 2020. "A GPR174–CCL21 module imparts sexual dimorphism to humoral immunity," Nature, Nature, vol. 577(7790), pages 416-420, January.
    2. Michael Koeppen & Jae W. Lee & Seong-Wook Seo & Kelley S. Brodsky & Simone Kreth & Ivana V. Yang & Peter M. Buttrick & Tobias Eckle & Holger K. Eltzschig, 2018. "Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    3. Minako Ito & Kyoko Komai & Setsuko Mise-Omata & Mana Iizuka-Koga & Yoshiko Noguchi & Taisuke Kondo & Ryota Sakai & Kazuhiko Matsuo & Takashi Nakayama & Osamu Yoshie & Hiroko Nakatsukasa & Shunsuke Chi, 2019. "Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery," Nature, Nature, vol. 565(7738), pages 246-250, January.
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    Cited by:

    1. Yingying Nie & Zeming Qiu & Sijia Chen & Zhao Chen & Xiaocui Song & Yan Ma & Niu Huang & Jason G. Cyster & Sanduo Zheng, 2023. "Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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