Brain vascular malformations and blood-brain barrier defects represent important substrates for developing stroke, epilepsy and other neurological diseases. The most common type of brain malformation closely associated with stroke are the cerebral cavernous malformations (CCMs), which affect approximately 0.5% of the population. Recognized as inherited and sporadic, CCMs are characterized as a single or multi-cluster of enlarged capillary-like channels with a single layer of endothelium and without intervening brain parenchyma. There are specific alterations in the brain endothelial barrier components that ultimately lead to vascular hyperpermeability, extravasation of red cells and a neuroinflammatory response. Although significant progress has been made in defining the genetic mutations involved in the inherited CCM3 form, the intra- and intercellular pathogenic mechanisms responsible for vascular injury are still largely unknown. One robust change in brain endothelial cell phenotype is a defect in cell polarity that affects the cell response to environmental stimuli and may progress the vascular injury. The proposed study is designed to elucidate critical molecular events involved in regulation of apicobasal polarity in CCM3 conditions. It will highlight the link between CCM3 and the cell polarity complex Par3/Par6/aPKC, identified by our screening analysis to be highly impacted by loss of CCM3 function in brain endothelial cells. Specifically, it will evaluate structural and functional alterations in the apicobasal polarity of brain endothelial cells in conditions of modified expression of CCM3 and CCM3 lesions. Collectively, these studies will provide information related to potential causes of leakiness and hemorrhage in CCM3 lesions, offer the new insights into the maintenance of brain endothelial barrier that is relevant also to multiple disease states and will, hopefully, elucidate novel therapeutic strategies to restore vascular permeability.