Semaglutide promotes angiogenesis and blood–brain barrier repair after traumatic brain injury via PDGF-BB/PDGFRβ/Ang1/Tie2/VEGF signaling pathway

Blood-brain barrier (BBB) repair and angiogenesis after traumatic brain injury (TBI) are pivotal for brain tissue repair. However, the mismatch between the initiation of angiogenesis and BBB integrity may contribute to aggravated edema and neuronal loss. Semaglutide (SEMA) has been validated in both basic and clinical studies for its neuroprotective efficacy against many neurological disorders. However, its intrinsic mechanisms governing BBB repair and angiogenesis remain undefined. A mouse controlled cortical impact (CCI) model was employed to investigate the effects of SEMA on BBB repair, angiogenesis, and the endothelial cell (EC)-pericyte (PC) axis. Key molecular markers and signaling pathways involved in these processes were detected and analyzed to clarify the underlying mechanisms of SEMA's protective effects. We revealed that SEMA upregulated platelet-derived growth factor-BB (PDGF-BB) expression in peri-lesional tissue. Increased PDGF-BB then acted on pericytes via platelet-derived growth factor receptor β (PDGFRβ), promoting the secretion of angiopoietin1 (Ang-1) and vascular endothelial growth factor (VEGF). This cascade not only promoted angiogenesis, but also enhanced the integrity of BBB by promoting the survival of PC and EC, upregulating tight junction proteins, which might eventually reduce brain edema and improve neurological function recovery after TBI. Mechanistically, PDGF-BB/PDGFRβ, ang1/Tie2, and PI3K/AKT pathways might be involved in SEMA mediated interactions between EC and PC. Collectively, our findings in this study elucidated the potential signaling mechanisms underlying SEMA-mediated blood-brain barrier protection and angiogenesis promotion, highlighting its potential as a TBI therapeutic targeting vascular homeostasis.