Advances in genetics, signaling, and modeling of venous malformations.

Vascular anomalies are defects resulting from the abnormal development or growth of the vasculature. Among these, venous malformations (VMs) are predominantly caused by mutations in the TIE2 or PIK3CA genes, which disrupt endothelial cell morphogenesis and vessel maturation. VM lesions are typically diagnosed during infancy or childhood and often persist and enlarge throughout adulthood, causing chronic complications such as pain, deformity, and coagulopathy. Despite available treatments such as sclerotherapy and mTOR inhibitors like sirolimus, achieving complete and long-term resolution of VMs remains a significant challenge. This review examines the genetic basis of VMs, explores the underlying molecular signaling mechanisms, and compares various experimental models-including in vitro, 3D, and in vivo systems-that have advanced our understanding of VM and provided platforms for testing potential therapies. Future research should prioritize the development of more precise and personalized models to drive improved strategies and better outcomes for patients with VMs.