Microglial Fkbp5 Impairs Post‐Stroke Vascular Integrity and Regeneration by Promoting Yap1‐Mediated Glycolysis and Oxidative Phosphorylation

Abstract The role of microglia in blood–brain barrier (BBB) leakage and neovascularization after ischemic stroke remains unclear. Here, a post‐stroke perivascular niche of microglia characterized by low expression of M2 markers and elevated glycolysis, oxidative phosphorylation (OXPHOS), and phagocytic activity is identified, which is termed stroke‐activated vascular‐associated microglia (stroke‐VAM). It is found that Fkbp5 acts as a central regulator driving BBB disruption and impaired neovascularization through stroke‐VAM. Single‐nucleus RNA sequencing (snRNA‐seq) analysis of Cx3cr1 Cre Fkbp5 flox/flox ( Fkbp5 cKO) mice in the ipsilateral hemisphere reveals enhanced interactions between stroke‐VAM and endothelial cells, influencing signaling pathways that maintain BBB integrity and promote neovascularization. After ischemic injury, microglia in Fkbp5 cKO mice exhibits higher M2 marker expression and reduces glycolysis, OXPHOS, and phagocytosis, resulting in decreased BBB leakage and enhanced angiogenesis. Mechanistically, unbiased snRNA‐seq analysis shows that the Hippo signaling pathway is altered in Fkbp5 cKO stroke‐VAM. Fkbp5 inhibits Yap1 phosphorylation, facilitating its nuclear translocation. These findings provide new insights into how the perivascular microglial niche contributes to both the degradation and regeneration of cerebral vasculature, offering potential therapeutic avenues for acute ischemic stroke.