Model of tPA signaling to occludin phosphorylation and BBB permeability. Ischemic stroke induces release of endogenous tPA that cleaves latent PDGF-CCL to active PDGF-CCa, which induces PDGFRα signaling in perivascular astrocytes. This results in decreased expression of ANGPTL4, relieving the ANGPTL4 inhibition of VEGF signaling, which further promotes ischemia-induced VEGF signaling through VEGFR2, which leads to activation of PKCβ and occludin phosphorylation on S490. This phosphorylation site regulates endocytosis of occludin with other junctional proteins, resulting in increased paracellular permeability. Recombinant thrombolytic tPA may leak into the brain parenchyma and further activate this system, leading to ICH when given beyond 4.5 hours after stroke. However, inhibiting PKCβ may provide a therapeutic option to maintain the BBB, extending the tPA therapeutic window. Note: Mural cell was retracted to emphasize VEGFR2 on the endothelial cell abluminal membrane.