Cellular Heterogeneity in Aortic Aneurysm and Dissection: Molecular Mechanisms and Therapeutic Opportunities

Aortic aneurysm and dissection (AAD) are life-threatening conditions characterized by progressive aortic dilation and acute aortic complications. Despite advances in surgical and endovascular management, effective pharmacological strategies to prevent AAD expansion and rupture are still lacking. The pathogenesis of AAD is increasingly understood to be driven by profound cellular heterogeneity within the aortic trilaminar wall, where diverse cell subpopulations contribute differentially to disease progression. This review integrates current evidence on how genetic predispositions, epigenetic modifications, clinical risk factors, and wall shear stress induce cellular heterogeneity, focusing on the pivotal roles of smooth muscle cells, endothelial cells, immune cells, and fibroblasts. We particularly highlight smooth muscle cell heterogeneity, which encompasses both distinct embryonic origins contributing to region-specific susceptibility to AAD, and dynamic phenotypic switching into fibroblast-like, proliferative, macrophage-like, osteochondrogenic, stressed, and adipocyte-like states. These phenotypic transitions, occurring in specific spatiotemporal patterns, critically drive extracellular matrix (ECM) degradation, inflammation, and metabolic reprogramming. Beyond smooth muscle cells, dysfunctional endothelial cells compromise barrier integrity through disruption of tight junctions (TJs), adherens junctions, and focal adhesions, facilitating leukocyte infiltration and procoagulant signaling. Diverse immune cell subsets, including heterogeneous monocytes/macrophages, eosinophils, and lymphoid cells, orchestrate complex inflammatory responses and mediate ECM breakdown. Furthermore, activated fibroblast subpopulations contribute to fibrotic remodeling and maintain close interactions with smooth muscle cells. Advances in single-cell multiomics and lineage-tracing technologies have been pivotal in unraveling the cellular complexity underlying AAD, uncovering novel disease mechanisms and cell-specific therapeutic targets. A comprehensive understanding of cellular heterogeneity, thus, holds the potential to develop precision medicine and offer promising therapeutic intervention for AAD.