Repair of the Cerebral Vasculature After Traumatic Brain Injury and the Influence of Beta-Catenin in New Vessel Formation and Injury Outcome
- Author(s): Salehi, Arjang
- Advisor(s): Obenaus, Andre;
- Zur Nieden, Nicole
- et al.
Traumatic brain injury (TBI) often results in damage to the cerebral vasculature which leads to hypoperfusion, edema, and hemorrhage. Repairing the injured vasculature after TBI is critical for neuroprotection and improving outcomes. While numerous studies have shown that the cerebral vessels are damaged after TBI, there are scant studies looking at repair of the vessel network following brain injury. Furthermore, there is a paucity of studies that have examined the molecular mechanisms underlying vascular repair after TBI. One possible signaling factor is β-catenin, which promotes blood vessel formation during embryonic development. To address this gap in knowledge, we developed a novel method to stain, visualize, and analyze the cerebral vasculature in the entire rodent brain. This technique, referred to as Vessel Painting (VP), effectively stains pial, penetrating, and parenchymal vessels and cerebral vessels can be imaged by wide-field fluorescent microscopy to acquire whole brain images. We introduce two complimentary methods to analyze vessel morphology and complexity in the whole brain. Our novel VP and analysis protocol was used to study the vascular alterations after TBI. Adult male mice received a moderate controlled cortical impact followed by VP at 1 and 7 days post injury (dpi). We assessed β-catenin inside blood vessels around the injury site and utilized a Wnt reporter mouse line (TCF/LEF:H2B-GFP) to monitor Wnt gene expression. We report that TBI results in vascular loss at 1 dpi followed by an increase in new vessels at 7 dpi. We observed an acute increase in β-catenin expression and increased Wnt reporter activity in cerebral vessels after TBI. To assess the role of β-catenin in vascular repair, we utilized Lithium to increase β-catenin expression and JW74 to reduce β-catenin expression. Lithium treatment after TBI enhanced vascular repair and lead to elongated vessel segments at 7 dpi while JW74 treatment after TBI reduced vascular repair and lead to fragmented vessels. Overall, these findings suggest that β-catenin becomes activated after TBI to initiate vascular repair. Treatment strategies to enhance β-catenin appear to contribute to vascular repair after TBI and represents a potential target for future therapeutics.