Endothelial YAP Signaling Promotes Blood-Spinal Cord Barrier Repair in Mice After Spinal Cord Injury.

After spinal cord injury (SCI), the blood-spinal cord barrier (BSCB) is disrupted, and endothelial cells, a critical component of BSCB, undergo proliferation and remodeling to maintain barrier integrity. However, the molecular mechanisms underlying BSCB remodeling remain unclear after SCI. Here, we reveal that Yes-associated protein (YAP), a principal downstream effector of the Hippo signaling pathway, promotes endothelial proliferation and BSCB repair in mice after SCI. First, we found that YAP expression was significantly upregulated and activated in endothelial cells after SCI. Endothelial YAP knockout (YAPTEK-cre/ERT2-CKO mice) impaired endothelial proliferation, endothelial-astrocyte end-feet reorganization, and tight junction (TJ) integrity, thereby aggravating BSCB disruption and impairing BSCB remodeling and motor functional recovery after SCI. Mechanistically, endothelial YAP-dependent BSCB repair was associated with angiopoietin-1 (ANGPT1) expression and PI3K/AKT pathway activation after SCI. Exogenous ANGPT1 treatment mitigated YAP deficiency-induced inhibition of endothelial proliferation and endothelial barrier disruption via PI3K/AKT signaling in vitro. Finally, activation of YAP signaling partially mitigated SCI-induced BSCB disruption, ultimately improving motor function recovery. Together, these results identify endothelial YAP signaling as a critical regulator of BSCB remodeling associated with ANGPT1/PI3K/AKT pathway and provide a potential therapeutic target for SCI.