Endothelial LRP1 activation mitigates microthrombosis after traumatic brain injury in mice

Traumatic brain injury (TBI) remains a pressing global health challenge, with microthrombosis emerging as a key pathological contributor to secondary brain damage. Through tissue disruption and multifaceted molecular cascades, TBI induces cerebral microthrombi formation, reducing local cerebral blood flow (CBF) and worsening neurological outcomes. However, effective strategies targeting this thrombotic complication are lacking, underscoring an urgent need for novel therapeutic approaches. Low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional receptor involved in vascular homeostasis, plays a central role in endothelial regulation, yet its therapeutic potential in post-TBI thrombosis remains underexplored. In this study, we systematically investigated the protective effects of LRP1 activation against TBI-induced microthrombosis using both in vivo and in vitro approaches. A murine TBI model was established via controlled cortical impact (CCI), followed by administration of the LRP1 agonist SP16. Behavioral assessments, immunohistochemistry, and immunoblotting revealed that TBI induced marked microthrombosis and endothelial hypercoagulability. SP16 treatment significantly reduced microthrombus burden, restored CBF perfusion, improved neurological recovery, and downregulated endothelial coagulation factors. Importantly, endothelial-specific LRP1 knockdown aggravated coagulation factor expression under pathological conditions. Mechanistically, SP16-mediated neuroprotection was at least partly dependent on endothelial LRP1 activation. These findings highlight LRP1 as a promising therapeutic target and position SP16 as a viable translational candidate for mitigating thrombotic complications and functional deficits following TBI.