ROBO4 is an endogenous inhibitor of VEGF signaling expressed by vascular endothelial cells37,38.This protein has been shown to dynamically maintain vascular network stability during pathological angiogenesis and proinflammatory processes39,40.In the FCCM cohort, an increase in plasma ROBO4 levels may reflect pro-inflammatory processes enhancing endothelial permeability, consistent with its prognostic association with CCM bleeding and growth8.E1/PAI-1 is a fast-acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA)41. Here, PLAU is linked to cerebral cavernous malformation.