Repair of the vasculature following TBI
Traumatic brain injury (TBI) research has largely focused on neuroprotective strategies, but these approaches have failed to develop any effective therapeutics in the clinic. Recently, a greater focus has been on understanding of the local environment of surviving neurons. One potential target has been the cerebral vasculature. TBI results in significant damage to the cerebral vessels and often leads to hemorrhage, edema, blood flow abnormalities, and ischemia, and cell death. An unexplored avenue is how blood vessels undergo repair. Previous studies suggest that there is delayed repair of the blood vessels following TBI which can lead to vascular abnormalities. Thus, a greater understanding of how the cerebral vasculature repairs following TBI could lead to development of new therapies that can enhance vascular repair, mitigate secondary effects, and potentially improve outcome.
We have developed and extended a novel vessel painting technique that effectively labels all the blood vessels in the rodent brain. One key advantage of this technique is that it allows for imaging of the cerebrovasculature over the entire brain or in specific regional areas. We are utilizing this technique to visualize the vascular alterations in the brain after moderate TBI. Our data reveals that TBI results in vascular loss followed by an increase in new blood vessels around the impact site by 7 days post injury (dpi) (Figure 1). Future research will focus on understanding the molecular mechanism(s) governing vascular repair.
Figure 1. Axial images of vessel painted vasculature at the peri-lesional tissue. We observed that a moderate controlled cortical impact elicits a loss of vasculature that extended beyond the TBI site (*). Note the fragmented vessels around the lesion border (arrows). Over the ensuing 7 dpi new vessels form around the impact site. White dotted line indicates lesion border. Scale bar = 200µm
Heme oxygenase-1 (HO-1) in TBI
Heme oxygenase-1 (HO-1) is an enzyme that catabolizes heme into carbon monoxide, biliverdin, and free iron. It is expressed in several tissues, including the liver, heart, and the brain. HO-1 has been known to be expressed following heat shock or oxidative stress. It is not known whether HO-1 serves a neuroprotective or neurodegenerative function after TBI. We will use an HO-1 overexpressing mouse model to see if additional HO-1 has an effect on lesion size and the amount of HO-1 expressing cells such as astrocytes and microglia.
Mild Traumatic Brain Injury in Pediatric Brain
Concussion or mild traumatic brain injury (mTBI) is a major public health concern often accompanied by long-term behavioral and neuropsychological deficits. However, despite overwhelming prevalence of TBI in children due to falls and sports-related accidents and the unique injury profile compared to that of adult TBI, the effects of mTBI on the developing brain have not been extensively examined. Studying alterations in white matter microstructure, myelination processes, and the vascular network that support such structure following mTBI in pediatric brain can not only provide us with valuable understanding of the pathophysiology of white matter injury in pediatric mTBI, but also open up new avenues for more effectively diagnosing and treating such injury. Using our closed head injury model, the TBI is delivered to the skull surface over the right cranium (as indicated by the red circle) creating both an initial rotation as a direct result of the impact (yellow arrow) followed by a secondary rotation of the brain (blue arrow). Our data demonstrates that single and repeated mTBI in pediatric brain leads to long term changes in behaviors, alterations in white matter microstructure that can be detected by diffusion tensor imaging (DTI) and immunohistochemistry, dysregulation of oligodendrocyte development, and changes in vasculature that supports white matter.