Endothelial tPA-dependent recruitment of microglia to vessels protects the blood-brain barrier after stroke in mice

Abstract

Thrombolysis with tissue-type plasminogen activator (tPA) remains the only pharmacological treatment for the acute phase of ischemic stroke. In this study, we hypothesize that endothelial tPA plays a key role in modulating the microglial response and maintaining blood brain barrier (BBB) integrity after stroke. Using a mouse model with conditional deletion for endothelial tPA (VeCadCre - tPAFlox) combined with a thrombotic stroke model and high-resolution imaging, we investigated the effects of endothelial tPA on vascular inflammation and microglia activation during the acute phase of stroke. Our results demonstrate that microglia-vessel contacts increase post-stroke. Notably, endothelial tPA deletion reduces vascular VCAM1 expression associated with decreased microglial activation and fewer microglia-vessel contacts. Following stroke, endothelial tPA deletion is associated with increased BBB permeability and heightened risk of haemorrhagic transformation. Collectively, these findings indicate that endothelial tPA mediates microglial recruitment to blood vessels, thereby exerting a protective effect on BBB integrity following ischemic stroke.