Developmental Endothelial Locus 1 Reduces Traumatic Brain Injury-Induced Endotheliopathy and Dysregulated Coagulation in Mice

Abstract

Background: Traumatic brain injury (TBI) induces endothelial injury (endotheliopathy) that disrupts the vascular barrier to cause cerebral hemorrhage and inflammation and allows the release of extracellular vesicles (EVs) from injured brain cells into the circulation. These EVs are highly procoagulant, causing a systemic hypercoagulable state that rapidly turns into consumptive coagulopathy. Protecting endothelial integrity and removing procoagulant EVs is, therefore, critical to preventing secondary cerebral and extracranial injuries from TBI.

Methods: We measured plasma Del-1 (developmental endothelial locus 1) levels in severe TBI mouse models and administered exogenous Del-1 pre-TBI or post-TBI to assess its effects on endotheliopathy, coagulopathy, and outcomes. Mechanistic studies involved administering exogenous Del-1 to TBI mice, followed by EV-scavenging analysis, and evaluating adhesion and apoptosis in Del-1-treated cultured endothelial cells, with key findings validated in both wild-type and Del-1-deficient mice.

Results: Plasma levels of Del-1 were reduced by 69% in mice subjected to severe TBI. Exogenous Del-1, given as either a preconditioning or a therapeutic agent, prevented mice with severe TBI from developing local and systemic endotheliopathy and coagulopathy, improving their outcomes. Del-1 protected TBI mice by scavenging anionic phospholipid-expressing EVs, including extracellular mitochondria from the circulation, by promoting endothelial cell adhesion and survival to protect endothelial integrity in wild-type and Del-1-deficient mice subjected to severe TBI.

Conclusions: This study demonstrates the importance of reducing anionic phospholipid-expressing EVs for TBI resuscitation and identifies Del-1 as a potential therapeutic agent to reduce EV-induced endotheliopathy and coagulopathy.

Keywords: coagulation dysregulation; developmental endothelial locus-1; endotheliopathy; extracellular vesicles; traumatic brain injury.