The vascular-osteogenic interface in craniofacial development: a structured review of emerging associations in...

Craniofacial skeletal morphogenesis depends on tightly coordinated interactions between vascular development and osteogenesis. Although congenital craniofacial malformations are traditionally conceptualized as bone-intrinsic disorders, emerging molecular evidence suggests that dysregulated vascular pathways may contribute to skeletal maldevelopment. Here, we synthesize emerging experimental and genetic evidence linking perturbations in vascular development to congenital craniofacial osseous phenotypes. A structured literature search was conducted in PubMed and Embase to identify experimental and genetic studies investigating developmental and vascular associations between vascular dysgenesis and craniofacial bone development. Six studies met the inclusion criteria. Within these studies, vascular dysgenesis was implicated in multiple craniofacial phenotypes. Hemifacial microsomia was linked to mandibular arterial abnormalities and susceptibility loci associated with vasculogenesis. Alagille syndrome demonstrated disrupted palatal vascular branching driven by Jagged1-Notch signaling perturbation. Across models, altered regulation of VEGF isoforms, Neuropilin-1, Jagged1-Notch signaling, and EPAS1-associated pathways impaired pharyngeal arch vascular remodeling, mandibular arterial stability, or vascular branching architecture. These vascular disturbances were associated with phenotypes including micrognathia, cleft palate, hemifacial microsomia, and 22q11.2 deletion syndrome-like features. In contrast, conditions including achondroplasia and cleidocranial dysplasia appear predominantly driven by bone-intrinsic mechanisms without demonstrated vascular involvement. Collectively, the available evidence suggests emerging developmental associations between dysregulated vascular signaling and craniofacial osteogenesis through a potential vascular-osteogenic interface. Although the temporal hierarchy, causality, and lineage-specific mechanisms remain unresolved, recognition of this interface provides a conceptual developmental perspective for future experimental studies investigating endothelial-osteogenic interactions during craniofacial morphogenesis.