Heart HealthTIE2 Receptor Circuit Drives Venous Malformation Growth Beyond PI3K Mutations
Venous malformations (VMs) are painful, disfiguring vascular lesions caused by mutations in PIK3CA or TIE2. Current treatments such as rapamycin reduce symptoms but rarely eliminate established lesions. This study reveals why: PI3K hyperactivity inactivates the transcription factor FOXO1, which normally drives expression of ANGPT2 — an endogenous TIE2 antagonist that brakes receptor activation. With ANGPT2 reduced and ANGPT1 increased from abnormally recruited smooth muscle cells, TIE2 stays persistently activated, fueling further vessel malformation. Blocking TIE2 or its ligands — rather than just mTOR — suppressed VM growth in mouse models, identifying a more effective therapeutic target.
