Improving blood flow and hindlimb function after chronic spinal cord injury in rats

Spinal Cord Injury (SCI) remains one of the foremost unsolved challenges in medicine. Currently, in the US there are approximately 300,000 persons living with chronic SCI with associated neurological and functional limitations that significantly reduce their quality of life. Therefore, it is imperative we understand the pathophysiology of the chronically injured spinal cord and develop therapies to enhance functional recovery in this patient population. The systemic effects of SCI include hypotension, reduced cardiac output, and impaired microcirculation in both gray matter (GM) and white matter (WM) of the spinal cord at the injury site. Insufficient blood distribution and flow can lead to disruptions in the blood spinal cord barrier (BSCB), loss of structural organization, endothelial cell death, and vascular remodeling. Although, extensive vascular alterations occur at the lesion site, the extent of vascular remodeling in distant areas remains unclear. In preliminary research, we found that intraspinal blood volume is compromised in rats at spinal segments below the lesion epicenter leads to hypoxia in the chronic phase of SCI. Loss of brainstem serotonin projections are thought to play a crucial role in this hypoxia. To characterize the extent of intraspinal vascular alteration as well as vascular responsiveness within the chronically injured spinal cord, we propose to utilize a recently developed technique called ultrafast contrast-enhanced ultrasound (CEUS) imaging. CEUS imaging allows for the visualization of morphology and blood flow velocities within larger vessels (>100 microns), as well as in the smaller microvasculature (<100 microns). Here, we aimed to determine how injury severity influence caudal spinal cord blood flow and serotonin input on the extent of this hypoperfusion. Interestingly, physical therapy has been shown to result in functional improvements after SCI in both clinical as well as pre-clinical studies, but it is unknown whether improved intraspinal vascular response and flow can be associated with these improvements. Moreover, the effects of physical therapy training are likely to be different between adult and middle-aged animals. Hence, we will determine whether age at the time of injury can affect vascular alterations and vascular responsiveness at the chronic stage. Results from this proposal are likely to yield critical information on vascular alterations in the chronically injury spinal cord and how vascular related mechanisms may support improved functional outcomes in adult and middle-aged patient populations after SCI.