Kisspeptin-54 Restores Blood-Brain Barrier Integrity via GATA-4 in Ischemic Stroke.

Ischemic stroke damages the blood-brain barrier (BBB), worsening neuronal injury. Treatments to protect the BBB are limited. We evaluated the neurovascular protective capacity of Kisspeptin-54 in ischemic stroke using in vivo and in vitro models. In vivo, mice underwent middle cerebral artery occlusion (MCAO), and cerebral infarct volume, neurological function, and blood-brain barrier (BBB) permeability were evaluated. In vitro, human brain microvascular endothelial cells (HBMVECs) were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to assess the effects of Kisspeptin-54 on paracellular flux and transendothelial electrical resistance (TEER). Additionally, GATA-4 was silenced to investigate its role in mediating protection. Our results showed that cortical ischemia downregulated KISS-1 metastasis-suppressor (KISS1, 59% mRNA; 55% protein) and G protein-coupled receptor 54 (GPR54, 54% mRNA; 48% protein), with a 32% decline in circulating Kisspeptin-54. Prophylactic Kisspeptin-54 reduced cerebral infarct volume by 42%, enhanced neurological performance by 49%, and decreased BBB leakage by 26%, with near-complete occludin recovery. In vitro: Kisspeptin-54 treatment reduced paracellular flux by 48% and increased transendothelial resistance by 60%. GATA-4 silencing abolished Kisspeptin-54-induced occludin restoration, increasing permeability by 65% and diminishing barrier resistance by 28%. This study reveals Kisspeptin-54 modulates BBB stability via GATA-4-driven occludin expression, highlighting the KISS1/GPR54 pathway as a potential therapeutic target for ischemic stroke.