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<p>Aortic dissection (AD) is a life-threatening vascular disease with a high mortality rate. Surgery is essential in the acute phase but carries significant risks, whereas elective surgery during the chronic phase yields better outcomes. However, no pharmacological therapy has been proven effective in slowing AD progression. In our recent pilot clinical study, an association between higher plasma fibrinogen levels and improved clinical outcomes was observed in AD patients, suggesting a potential protective role of fibrinogen. However, direct evidence supporting this hypothesis is lacking. In this study, a population-based analysis of nonsurgically managed patients with acute AD revealed a distinct association: fibrinogen levels &lt;2 g/L were significantly associated with increased mortality, whereas levels &gt;4 g/L were significantly associated with reduced mortality. Notably, fibrinogen was undetectable in aortic samples from control individuals without AD but accumulated in the aortic media of both AD patients and model mice. Importantly, fibrinogen accumulation was more pronounced in mice with advanced but unruptured AD, suggesting its role in maintaining vascular stability. AAV8-mediated fibrinogen knockdown significantly exacerbated AD, whereas exogenous supplementation with fibrinogen alleviated AD in mice, as evidenced by changes in the survival rate, aortic dilation, AD incidence, elastic fiber degradation, and collagen accumulation. Mechanistically, fibrinogen inhibited Bmal1 signaling, preventing detrimental vascular smooth muscle cell (VSMC) phenotypic transformation and contractility impairment. Finally, exogenous supplementation with the optimal dose of fibrinogen mitigates the progression of AD in mice. This study identified fibrinogen as a key regulator of VSMC contractility and aortic structural integrity, highlighting its potential as a novel therapeutic target to delay AD progression and extend the window for elective surgery.</p>

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Fibrinogen–Bmal1 signaling as a therapeutic target to limit aortic dissection by preserving VSMC contractility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Xiaohan Zhong,
  • Dongjie Li,
  • Yuanfei Zhao,
  • Lu Dai,
  • Jinzhang Li,
  • Zhiqi Ji,
  • Bojing Zuo,
  • Hongshan Liu,
  • Haixia Huang,
  • Wei Wang,
  • Haiyang Li,
  • Yuyong Liu,
  • Ming Gong,
  • Xinliang Ma,
  • Wenjian Jiang,
  • Meili Wang,
  • Hongjia Zhang

摘要

Aortic dissection (AD) is a life-threatening vascular disease with a high mortality rate. Surgery is essential in the acute phase but carries significant risks, whereas elective surgery during the chronic phase yields better outcomes. However, no pharmacological therapy has been proven effective in slowing AD progression. In our recent pilot clinical study, an association between higher plasma fibrinogen levels and improved clinical outcomes was observed in AD patients, suggesting a potential protective role of fibrinogen. However, direct evidence supporting this hypothesis is lacking. In this study, a population-based analysis of nonsurgically managed patients with acute AD revealed a distinct association: fibrinogen levels <2 g/L were significantly associated with increased mortality, whereas levels >4 g/L were significantly associated with reduced mortality. Notably, fibrinogen was undetectable in aortic samples from control individuals without AD but accumulated in the aortic media of both AD patients and model mice. Importantly, fibrinogen accumulation was more pronounced in mice with advanced but unruptured AD, suggesting its role in maintaining vascular stability. AAV8-mediated fibrinogen knockdown significantly exacerbated AD, whereas exogenous supplementation with fibrinogen alleviated AD in mice, as evidenced by changes in the survival rate, aortic dilation, AD incidence, elastic fiber degradation, and collagen accumulation. Mechanistically, fibrinogen inhibited Bmal1 signaling, preventing detrimental vascular smooth muscle cell (VSMC) phenotypic transformation and contractility impairment. Finally, exogenous supplementation with the optimal dose of fibrinogen mitigates the progression of AD in mice. This study identified fibrinogen as a key regulator of VSMC contractility and aortic structural integrity, highlighting its potential as a novel therapeutic target to delay AD progression and extend the window for elective surgery.