Endothelial Bmal1 coordinates intrinsic and paracrine mechanisms to limit post-injury vascular restenosis.
6 affiliations
- 1Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
- 2Health Science Center, East China Normal University, Shanghai, 200241, China. [email protected].
- 3College of Basic Medical Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
- 4Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. [email protected].
- 5Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China. [email protected].
- 6Health Science Center, East China Normal University, Shanghai, 200241, China. [email protected].
Abstract
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
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03116-3.
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BibTeX
@article{liang2026endothelial,
title = {{Endothelial Bmal1 coordinates intrinsic and paracrine mechanisms to limit post-injury vascular restenosis.}},
author = {Qing Liang and Hu Xu and Ruqiang Yuan and Min Liu and Lei Qian and Jiajia Yi and Guangrui Yang and Qingyong He and Lihong Chen},
journal = {Cell communication and signaling : CCS},
year = {2026},
month = aug,
doi = {10.1186/s12964-026-03116-3},
url = {https://europepmc.org/article/MED/42968094},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Endothelial Bmal1 coordinates intrinsic and paracrine mechanisms to limit post-injury vascular restenosis.
AU - Qing Liang
AU - Hu Xu
AU - Ruqiang Yuan
AU - Min Liu
AU - Lei Qian
AU - Jiajia Yi
AU - Guangrui Yang
AU - Qingyong He
AU - Lihong Chen
PY - 2026
DA - 2026/08/05
JO - Cell communication and signaling : CCS
DO - 10.1186/s12964-026-03116-3
UR - https://europepmc.org/article/MED/42968094
AB - 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 Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03116-3.
SN - 1478-811X
ER -