Aortic dissection as a disease of vascular wall homeostasis: integrating vasa vasorum-inflammation-metabolism axis for mechanistic insight and clinical translation.

Aortic dissection (AD) has traditionally been viewed as an acute structural failure initiated by an intimal tear. However, accumulating evidence suggests that this catastrophic event represents the endpoint of a prolonged, multiscale process of vascular wall homeostatic imbalance. In this review, we propose an integrative framework in which AD arises from the progressive destabilization of a tightly coupled system involving endothelial function, vascular smooth muscle cell phenotype, extracellular matrix integrity, and vasa vasorum dynamics. Central to this model is the vascular-inflammation-metabolism axis, where microvascular dysfunction induces hypoxia, metabolic reprogramming, and oxidative stress, thereby triggering inflammatory amplification and matrix degradation. These processes interact through nonlinear feedback loops, gradually reducing the mechanical resilience of the aortic wall and driving it toward a critical transition. Importantly, the intimal tear is redefined not as the primary cause but as the final manifestation of underlying biological instability. This systems-level perspective reconciles clinical heterogeneity, including variable susceptibility, diverse disease trajectories, and cases lacking clear primary tears. By linking molecular, cellular, and biomechanical mechanisms into a unified framework, this model provides a foundation for identifying early biomarkers, refining risk stratification, and developing targeted therapeutic strategies aimed at restoring vascular homeostasis before catastrophic failure occurs.