ABSTRACT: Background: Coarctation of the aorta (CoA) is a congenital narrowing of the aortic isthmus, typically located near the ductus arteriosus or ligamentum arteriosum. Despite successful anatomical repair, affected individuals remain at risk of recoarctation, arterial hypertension, and diffuse aortopathy, suggesting that CoA involves intrinsic abnormalities of the vessel wall beyond a localized mechanical obstruction. The developmental and molecular mechanisms underlying this vascular phenotype remain incompletely understood. Results: Transcriptomic profiling identified 402 transcripts separating CoA from control tissue. Canonical pathway analysis showed a dominant extracellular matrix and collagen-remodeling signature, including collagen biosynthesis and modification, collagen degradation, integrin-mediated cell–matrix interaction, wound-healing-associated signaling, and fibrosis-like remodeling programs. In parallel, developmental patterning pathways were retained, including RAR/RXR-associated signaling, anterior HOX developmental annotations, and a shared HOX/MEIS signature. Network and upstream regulator analyses supported convergence of extracellular matrix, collagen, cytoskeletal, and muscle-associated modules with developmental and epigenetic regulators, including KAT6A, KAT6B, RAR/RXR/retinoic acid, DNMT3B, KMT2A, and ARID1A. RT-qPCR follow-up demonstrated increased expression of EDN1, AGTR2, IRS4, and TFAP2B, whereas selected pathway-derived candidates, including TGFB, were not confirmed. Conclusions: Infantile CoA tissue displayed a dominant vessel-wall remodeling phenotype accompanied by RA/HOX/MEIS-associated developmental patterning, smooth muscle/cytoskeletal regulatory programs, and selected vascular signaling changes. These findings support a developmental-remodeling model in which retained or reactivated positional-identity programs at the neural crest-ductus-aortic isthmus interface coexist with postnatal extracellular matrix remodeling. The data provide a hypothesis-generating molecular framework for understanding CoA as a localized congenital vascular lesion with persistent developmental and remodeling features.
