Endothelial miR-15a/16-1 Regulation of SYNE1 Mediates Structural and Functional Recovery after Traumatic Brain Injury.

Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB) and compromises endothelial function, leading to persistent neurological dysfunction. Although miR-15a/16-1 deletion has recently been shown to be neuroprotective in brain injury, the endothelial pathways mediating long-term structural and functional recovery after TBI remain unknown. Here, we demonstrate endothelial cell-specific deletion of miR-15a/16-1 is sufficient to confer neurorestoration after TBI by reducing acute BBB leakage, preserving white and gray matter integrity, and accelerating sensorimotor and cognitive recovery. Mechanistically, transcriptomic profiling identified SYNE1 as a direct downstream target of miR-15a/16-1, validated via in-silico binding prediction and 3'-UTR luciferase assays. Crucially, endothelial cell-targeted AAV-mediated knockdown of SYNE1 abrogated the neurorestorative effects of miR-15a/16-1 deletion, indicating SYNE1 is required for its function. Furthermore, single-cell RNA-seq analysis of human TBI tissue demonstrates significant downregulation of SYNE1 in endothelial cells within the contusion core relative to pericontusional endothelium. Together, these findings define a previously unrecognized miR-15a/16-1-SYNE1 axis that promotes endothelial repair after TBI, with significant translational potential.