Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Significance Blood–brain barrier (BBB) breakdown is a catastrophic event in the pathogenesis of various neurological disorders, including stroke. Here we report that overexpressing heat shock protein 27 (HSP27) specifically within microvascular endothelial cells protects the BBB in models of ischemic stroke. HSP27 achieves this protection through a previously unexplored mechanism—the inhibition of actin polymerization—that suppresses early structural changes within endothelial cells that appear to initiate the BBB breach. Furthermore, intravenous delivery of a cell membrane-permeable TAT-HSP27 protein after postischemic reperfusion boosts endothelial HSP27 and improves BBB integrity and long-term functional outcomes. Thus, HSP27 has translational potential as a therapeutic agent to ameliorate BBB disruption, reduce the progression of brain injury, and improve long-term neurological outcomes in stroke victims.