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Background <p>Circadian rhythms have been implicated in the regulation of cardiovascular physiology and disease. Disruption of circadian signaling has been linked to exaggerated neointimal hyperplasia and delayed endothelial repair. Bmal1, a core component of the molecular clock, plays a critical role in maintaining vascular homeostasis. However, the specific contribution of endothelial cell (EC)-derived Bmal1 to post-injury neointimal hyperplasia remains unclear. This study aims to elucidate the role and mechanisms of EC-derived Bmal1 in vascular restenosis.</p> Methods and results <p>EC-specific Bmal1 knockout mice (Bmal1<sup>f/f</sup>-Tie2<sup>Cre+</sup> and Bmal1<sup>f/f</sup>-Cdh5<sup>Cre+</sup>) and their littermate controls (Bmal1<sup>f/f</sup>) were subjected to carotid artery ligation and femoral artery wire injury models. EC-Bmal1 deficiency significantly aggravated neointimal hyperplasia, impaired re-endothelialization, enhanced leukocyte infiltration, and promotes vascular smooth muscle cell (VSMC) phenotypic modulation. Mechanistically, loss of EC-Bmal1 reduced endothelial proliferation, migration, and angiogenic capacity. Moreover, EC-Bmal1 deficiency was associated with activation of NF-κB signaling, leading to upregulated expression and secretion of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and other endothelial-derived mediators. IL-6 promotes VSMC phenotypic modulation via the PKA signaling axis, while ICAM-1 facilitated monocyte adhesion through activation of the phosphorylated JNK signaling. These intrinsic and paracrine mechanisms synergistically contributed to vascular remodeling after injury.</p> Conclusions <p>Our study identifies a protective role of EC-Bmal1 in limiting injury-induced vascular restenosis and suggests that endothelial Bmal1 may represent a potential therapeutic target for preventing restenosis after percutaneous coronary intervention.</p> Graphical abstract <p>In wild-type mice with intact endothelial Bmal1 expression, vascular injury induces only moderate ICAM-1 and IL-6 expression, thereby maintaining controlled repair responses. In contrast, in EC-Bmal1-KO mice, endothelial Bmal1 deficiency not only suppresses endothelial proliferation and migration, impairing regeneration, but also drives paracrine NF-κB–mediated upregulation of ICAM-1 and IL-6, which promotes monocyte infiltration, macrophage activation, and VSMC remodeling, collectively exacerbating restenosis</p> <p></p>

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Endothelial Bmal1 coordinates intrinsic and paracrine mechanisms to limit post-injury vascular restenosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Qing Liang,
  • Hu Xu,
  • Ruqiang Yuan,
  • Min Liu,
  • Lei Qian,
  • Jiajia Yi,
  • Guangrui Yang,
  • Qingyong He,
  • Lihong Chen

摘要

Background

Circadian rhythms have been implicated in the regulation of cardiovascular physiology and disease. Disruption of circadian signaling has been linked to exaggerated neointimal hyperplasia and delayed endothelial repair. Bmal1, a core component of the molecular clock, plays a critical role in maintaining vascular homeostasis. However, the specific contribution of endothelial cell (EC)-derived Bmal1 to post-injury neointimal hyperplasia remains unclear. This study aims to elucidate the role and mechanisms of EC-derived Bmal1 in vascular restenosis.

Methods and results

EC-specific Bmal1 knockout mice (Bmal1f/f-Tie2Cre+ and Bmal1f/f-Cdh5Cre+) and their littermate controls (Bmal1f/f) were subjected to carotid artery ligation and femoral artery wire injury models. EC-Bmal1 deficiency significantly aggravated neointimal hyperplasia, impaired re-endothelialization, enhanced leukocyte infiltration, and promotes vascular smooth muscle cell (VSMC) phenotypic modulation. Mechanistically, loss of EC-Bmal1 reduced endothelial proliferation, migration, and angiogenic capacity. Moreover, EC-Bmal1 deficiency was associated with activation of NF-κB signaling, leading to upregulated expression and secretion of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and other endothelial-derived mediators. IL-6 promotes VSMC phenotypic modulation via the PKA signaling axis, while ICAM-1 facilitated monocyte adhesion through activation of the phosphorylated JNK signaling. These intrinsic and paracrine mechanisms synergistically contributed to vascular remodeling after injury.

Conclusions

Our study identifies a protective role of EC-Bmal1 in limiting injury-induced vascular restenosis and suggests that endothelial Bmal1 may represent a potential therapeutic target for preventing restenosis after percutaneous coronary intervention.

Graphical abstract

In wild-type mice with intact endothelial Bmal1 expression, vascular injury induces only moderate ICAM-1 and IL-6 expression, thereby maintaining controlled repair responses. In contrast, in EC-Bmal1-KO mice, endothelial Bmal1 deficiency not only suppresses endothelial proliferation and migration, impairing regeneration, but also drives paracrine NF-κB–mediated upregulation of ICAM-1 and IL-6, which promotes monocyte infiltration, macrophage activation, and VSMC remodeling, collectively exacerbating restenosis