PDZRN3 destabilizes endothelial cell-cell junctions through a PKCζ-containing polarity complex to increase vascular permeability

Interconnected endothelial cells that line blood vessels form a barrier between the circulatory system and tissues. The integrity of the intercellular junctions between endothelial cells regulates vascular permeability, which is the leakiness of blood vessels. In stroke patients, too much fluid can accumulate in the brain and cause irreparable damage. Sewduth et al . elucidated a signaling pathway mediated by the E3 ubiquitin ligase PDZRN3 that regulated endothelial intercellular junctions and vascular permeability. Developing mice that overexpressed Pdzrn3 in endothelial cells died of hemorrhaging in multiple tissues, whereas genetic ablation of Pdzrn3 in adult mice decreased the brain edema that occurred after stroke, an effect mimicked by a pharmacological inhibitor of PKCζ, a kinase that destabilizes endothelial intercellular junctions. Manipulating Pdzrn3 abundance in endothelial cells affected the localization of PKCζ to intercellular junctions, activation of PKCζ, and permeability. These results suggest that inhibiting PDZRN3 or its downstream effector PKCζ may prevent the pathological edema that occurs in conditions such as stroke.