Title : Studies on traumatic brain injury: Fragments of VWF regulate the expression of adhesion molecules and modulate vascular permeability in stimulated endothelial cells
Von Willebrand factor (VWF) is a multimeric protein that mediates thromboinflammation and has been linked to traumatic brain injury (TBI), specifically in the pathogenesis of early brain injury. Activated endothelium secretes VWF multimers as long hyperadhesive strings. During TBI, the expression of hyperadhesive strings increase significantly. ADAMTS13, a disintegrin and metalloprotease with thrombospondin type-1 repeats, member 13, is a proteolytic factor that reduces the hyperadhesive VWF strings to less adhesive form by cleaving the VWF strings at the A2 domain. In fact, there are experimental studies demonstrating the beneficial effect of intervening with ADAMTS13 after TBI in mice. However, whether the proteolytic fragments of VWF attenuate the severity of TBI remains unknown. Therefore, our research focuses on elucidating the mechanisms by which VWF fragments may regulate the permeability of stimulated endothelium. Fragments of VWF regulate permeability in endothelial cells and play a role in vascular permeability in a TBI mouse model. We employed recombinant proteins encompassing the amino acid sequence of the A1A2A3 domains of VWF. We used biolayer interferometry, immunofluorescence and immunohistochemistry approaches to analyze vascular permeability during endothelial stimulation. The data shows that Fragments of VWF (A1A2A3 WT and A1A2A3 GOF) modulated permeability, altering the morphology of VE-cadherin, β-actin, and ZO-1. A1A2A3 GOF fragment shown to be effective to rescue permeability at 24 hrs in human microvascular endothelial cells under stimulation with IL-1β. In addition, we noticed a decreased expression of VWF on a mouse brain microvessels after 3 weeks of TBI insult. Based on our experimental data we conclude that VWF is essential to maintain vascular permeability. Our future direction is to evaluate the role of VWF fragments employing a TBI mouse model.
Audience Take Away
- This presentation will help to understand the mechanisms mediated by VWF in the control of vascular permeability. People who work with TBI can expand their work in order to develop better treatments for people who suffer from this condition. Teachers could develop lines of research for other drugs that can be used to improve the quality of life of these people
- Whether this would help focus research on agents that help improve brain damage caused by TBI
- This research is focused on the veteran population, but this information can benefit children and young athletes or people who have suffered a severe brain accident
- Today there are not enough treatments to help restore brain damage and this study aims to find new markers with the potential to reduce damage and prevent brain leaks