Jing Tao, Huanjie Yang, Jiahui Yong, X Chen, Qiang Zhao, Xueli Wu, Lei Yan, Li Pang, Fan Luo, Mengjun Yu, Shanshan Pan, Deyang Li, R Y Chen, Yi-Xiang Wang, Zhensheng Dong, Fan Yang, Yue Wang, Yang Chen, Hongjian Zheng, Zhimin Yang, Zijie Wang, Karsten Kristiansen, Hui Peng, Xiaodong Fang, Juan Shen, Yi‐Ning Yang
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 (Fibro_C1_FBN1+; 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.