Abstract
<jats:p>Sporadic ascending aortic dissection (AAD) carries high short-term mortality and long-term morbidity. Hypertension is the predominant risk factor, yet no established tools identify patients at imminent risk. Although medial vulnerability likely contributes to dissection in heritable aortopathies, AAD predominantly understood as a luminal breach followed by false-lumen propagation, with comparatively less emphasis on the underlying medial substrate. We sought to define the vascular smooth muscle cell (VSMC) landscape in human AAD and identify spatial remodeling programs associated with interlamellar separation. Using Xenium in situ spatial transcriptomic profiling, we generated cellular-resolution maps of the dissected human ascending aorta. We identified extensive VSMC remodeling organized into distinct laminar domains across the aortic media, with distinct VSMC states supported by gene-expression module scoring and trajectory analysis. A reproducible mid-medial core of chronically hypoxia-adapted VSMCs was identified across patients and supported by carbonic anhydrase 9 immunohistochemistry. These hypoxia-adapted VSMCs lacked inflammatory and immediate-early activation programs and were spatially distinct from stress-responsive VSMC states enriched along the false lumen. Circumferential profiling in a complete aortic ring demonstrated greater adaptive remodeling in the outer curve compared with the inner curve. In contrast, donor control aortas contained fewer modulated VSMC states, less laminar striation, and no comparable hypoxia-adapted core. These findings define a spatially organized medial remodeling landscape in AAD and identify hypoxia-associated VSMC modulation as a potential feature of medial domains associated with heightened vulnerability to interlamellar separation. Defining these remodeling domains may inform improved risk stratification and experimental models that better recapitulate human AAD pathology.</jats:p>