Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling

Yusuke Adachi, Kazutaka Ueda (), Seitaro Nomura, Kaoru Ito, Manami Katoh, Mikako Katagiri, Shintaro Yamada, Masaki Hashimoto, Bowen Zhai, Genri Numata, Akira Otani, Munetoshi Hinata, Yuta Hiraike, Hironori Waki, Norifumi Takeda, Hiroyuki Morita, Tetsuo Ushiku, Toshimasa Yamauchi, Eiki Takimoto and Issei Komuro ()
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Yusuke Adachi: Graduate School of Medicine, The University of Tokyo
Kazutaka Ueda: Graduate School of Medicine, The University of Tokyo
Seitaro Nomura: Graduate School of Medicine, The University of Tokyo
Kaoru Ito: RIKEN Center for Integrative Medical Sciences
Manami Katoh: Graduate School of Medicine, The University of Tokyo
Mikako Katagiri: Graduate School of Medicine, The University of Tokyo
Shintaro Yamada: Graduate School of Medicine, The University of Tokyo
Masaki Hashimoto: Graduate School of Medicine, The University of Tokyo
Bowen Zhai: Graduate School of Medicine, The University of Tokyo
Genri Numata: Graduate School of Medicine, The University of Tokyo
Akira Otani: Graduate School of Medicine, The University of Tokyo
Munetoshi Hinata: The University of Tokyo
Yuta Hiraike: The University of Tokyo
Hironori Waki: The University of Tokyo
Norifumi Takeda: Graduate School of Medicine, The University of Tokyo
Hiroyuki Morita: Graduate School of Medicine, The University of Tokyo
Tetsuo Ushiku: The University of Tokyo
Toshimasa Yamauchi: The University of Tokyo
Eiki Takimoto: Graduate School of Medicine, The University of Tokyo
Issei Komuro: Graduate School of Medicine, The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.

Date: 2022
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DOI: 10.1038/s41467-022-32658-6

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