PI3KC2? inactivation stabilizes VE-cadherin junctions and preserves vascular integrity

Endothelium protection is critical, because of the impact of vascular leakage and edema on pathological conditions such as brain ischemia. Whereas deficiency of class II phosphoinositide 3-kinases alpha (PI3KC2?) results in an increase in vascular permeability, we uncover a crucial role of the beta isoform (PI3KC2?) in the loss of endothelial barrier integrity following injury. Here, we studied the role of PI3KC2? in endothelial permeability and endosomal trafficking in vitro and in vivo in ischemic stroke. Mice with inactive PI3KC2? showed protection against vascular permeability, edema, cerebral infarction, and deleterious inflammatory response. Loss of PI3KC2? in human cerebral microvascular endothelial cells stabilized homotypic cell-cell junctions by increasing Rab11-dependent VE-cadherin recycling. These results identify PI3KC2? as a potential new therapeutic target to prevent aggravating lesions following ischemic stroke.