ABSTRACT Although single‐cell studies have profiled diseased aorta, mechanisms driving aortic dissection (AD) remain largely elusive owing to limited cohorts. Here, we integrate single‐cell and spatial transcriptomic data from 110 thoracic aortic samples (80 individuals; control, aneurysm, dissection; 767 018 high‐quality cells) to generate a comprehensive thoracic‐aorta cellular—molecular atlas. We identify an elastin‐rich fibroblast subset (FibroC1FBN1+; FBN1, MFAP5, LOX) that declines with age and is markedly depleted in AD, linking fibroblast loss to increased aortic wall vulnerability and dissection risk. Vascular smooth muscle cells (vSMCs) undergo ENO1 ‐driven glycolytic reprogramming under hypoxia, lose contractility and adopt a synthetic, MIF ‐secreting phenotype that engages macrophage receptors to promote macrophage recruitment and pro‐inflammatory polarization, leading aggregated macrophages to upregulate proteolytic and fibrinolytic pathways and thereby accelerate extracellular‐matrix degradation. In vitro and in vivo, ENO1 knockdown inhibits vSMC switching, reduces macrophage inflammation, and slows AD progression. This stromal‐immune axis suggests potential therapeutic targets in AD.
Tao et al. (Sun,) studied this question.