Single-cell lineage tracing unveils sex differences in VSMCs derived from the cardiac neural crest and second heart field

Vascul Pharmacol. 2026 Jun;163:107611. doi: 10.1016/j.vph.2026.107611. Epub 2026 Apr 30.

ABSTRACT

Stanford type A thoracic aortic aneurysm and dissection (TAAD) affects the ascending aorta and aortic arch and can cause sudden death due to rupture. Epidemiological studies have shown that TAAD occurs more frequently in men than women. Vascular smooth muscle cells (VSMCs) are one of the major cell types in the vascular wall and play a critical role in the pathogenesis of TAAD. Recent studies have highlighted the developmental heterogeneity of VSMCs in the ascending aorta and aortic arch, which are derived primarily from the second heart field (SHF) and cardiac neural crest (CNC), respectively. However, whether sex influences the biological properties of these lineage-specific VSMCs and thereby contributes to TAAD susceptibility remains poorly understood. In this study, we generated Wnt1-Cre/Rosa26-mTmG lineage-tracing reporter mice and performed single-nucleus RNA sequencing using the ascending aortae and aortic arch from both sexes. Our results showed that male VSMCs exhibited higher expression of genes associated with maintenance of contractility, whereas female VSMCs preferentially expressed genes involved in extracellular matrix (ECM) organization. Together, these data suggest that the ascending aorta and aortic arch in females may exhibit greater mechanical resilience, which partially account for the lower incidence of TAAD in women.

PMID:42069076 | DOI:10.1016/j.vph.2026.107611