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<p>Aortic dissection (AD) is a devastating vascular disorder pathologically characterized by pathological phenotypic switching of medial vascular smooth muscle cells (VSMCs) and progressive breakdown of extracellular matrix (ECM) architecture. Conventional paradigms have primarily emphasized unidirectional injury originating within the vessel wall. Nevertheless, accumulating evidence indicates that perivascular adipose tissue (PVAT), which directly envelops the adventitia and is increasingly regarded as the “fourth layer” of the vascular wall, exerts a critical outside-in influence on vascular homeostasis and microenvironmental imbalance. This review systematically delineates how perivascular adipose tissue (PVAT) shifts from a vasoprotective component to a pathogenic source under conditions of local inflammation or metabolic stress. We particularly focus on the pathological state in which PVAT releases a broad array of pro-inflammatory mediators through paracrine signaling, most notably transforming growth factor-β1 (TGF-β1), which crosses tissue boundaries to orchestrate microenvironmental crosstalk between the adventitia and the media.Under persistent TGF-β1 stimulation, vascular smooth muscle cells (VSMCs) may develop a cooperative transcriptional regulatory network centered on Runt-related transcription factor 1 (RUNX1) and nuclear factor-κB (NF-κB). This review explores the hypothesis that PVAT-derived inflammatory stimuli may induce post-receptor TGF-β1 signal shunting, thereby favoring the formation of a RUNX1/NF-κB regulatory axis in VSMCs. Such a network may contribute to aortic wall destabilization by suppressing contractile phenotype-associated genes while promoting inflammatory and extracellular matrix remodeling programs. From an “outside-in” perspective, we discuss the potential role of PVAT–VSMC microenvironmental crosstalk in AD pathogenesis and critically evaluate the current evidence supporting this model, as well as its limitations. Furthermore, we propose that future therapeutic strategies targeting this transcriptional axis may require localized delivery approaches to minimize systemic adverse effects, including bleeding and immunosuppression, thereby offering a potential avenue for precision treatment of AD.</p>

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The critical role of the RUNX1/NF-κB transcriptional complex–mediated PVAT–VSMC axis in aortic dissection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Xin Guo,
  • Baohui Liu,
  • Yuexin Han,
  • Xizeng Si,
  • Yifan Zhou,
  • Yujiu Wang

摘要

Aortic dissection (AD) is a devastating vascular disorder pathologically characterized by pathological phenotypic switching of medial vascular smooth muscle cells (VSMCs) and progressive breakdown of extracellular matrix (ECM) architecture. Conventional paradigms have primarily emphasized unidirectional injury originating within the vessel wall. Nevertheless, accumulating evidence indicates that perivascular adipose tissue (PVAT), which directly envelops the adventitia and is increasingly regarded as the “fourth layer” of the vascular wall, exerts a critical outside-in influence on vascular homeostasis and microenvironmental imbalance. This review systematically delineates how perivascular adipose tissue (PVAT) shifts from a vasoprotective component to a pathogenic source under conditions of local inflammation or metabolic stress. We particularly focus on the pathological state in which PVAT releases a broad array of pro-inflammatory mediators through paracrine signaling, most notably transforming growth factor-β1 (TGF-β1), which crosses tissue boundaries to orchestrate microenvironmental crosstalk between the adventitia and the media.Under persistent TGF-β1 stimulation, vascular smooth muscle cells (VSMCs) may develop a cooperative transcriptional regulatory network centered on Runt-related transcription factor 1 (RUNX1) and nuclear factor-κB (NF-κB). This review explores the hypothesis that PVAT-derived inflammatory stimuli may induce post-receptor TGF-β1 signal shunting, thereby favoring the formation of a RUNX1/NF-κB regulatory axis in VSMCs. Such a network may contribute to aortic wall destabilization by suppressing contractile phenotype-associated genes while promoting inflammatory and extracellular matrix remodeling programs. From an “outside-in” perspective, we discuss the potential role of PVAT–VSMC microenvironmental crosstalk in AD pathogenesis and critically evaluate the current evidence supporting this model, as well as its limitations. Furthermore, we propose that future therapeutic strategies targeting this transcriptional axis may require localized delivery approaches to minimize systemic adverse effects, including bleeding and immunosuppression, thereby offering a potential avenue for precision treatment of AD.