Differential microvascular response to trauma in the spinal cord with sex and age

University Of Washington, Seattle WA

Investigators

Abstract

Abstract Currently, there is no known treatment to limit and/or protect the injured spinal cord from secondary damage in patients with spinal cord injury (SCI). More than 60% of SCIs occur at the cervical level, resulting in respiratory dysfunction and quadriplegia (paralysis of all four limbs), severely affecting patients’ quality of life. The older population (≥65 years old) represents the fastest growing age group in the United States. In recent years, ground level falls resulting in SCIs are among the most common trauma suffered by older patients presenting to the emergency room, and over 90% of all SCI in the aged population are at the cervical level. Alarmingly, little is known about how trauma induced changes in microvascular density can render the aged spinal cord more vulnerable to ischemic damage. We hypothesize that there is a significant reduction in the microvascular response to trauma in the cervical spine with aging, and that this results in increased vulnerabilities. The overall objective of this proposal is to examine and evaluate critical microvascular blood flow parameters that can reduce cervical spinal tissue loss for improved functional recovery after cervical SCI in a rodent model. Acutely after traumatic SCI, a complete loss of blood flow occurs at the injury center and is thought to be a major contributor to the injury expansion during the secondary phase. Improving blood flow to the lesion center and adjacent tissue has long been considered desirable to mitigate the loss of neural tissue. We have developed and used a novel intravital ultrafast ultrasound imaging technique to visualize spinal blood flow in real-time with unprecedented spatial and temporal resolution. Recent work from our group has shown that ultrafast ultrasound can 1) detect distinct areas of perfusion loss in both the grey and white matter, 2) evaluate the quality of peri-lesional blood flow, and 3) visualize patent spinal vessel morphology (down to ~ 50 micrometer) in a clinically relevant rat cervical SCI model. Excitingly, we have developed non-invasive 3D image acquisitions, allowing us to monitor blood flow changes within the injured spinal cord in 4D (3D imaging with time) in a well-established model of aging in rats. We hypothesize that improving microvascular flow and pericyte function and coverage after SCI in the aged rat can improve spinal tissue perfusion and mitigate secondary tissue loss for improved functional outcomes. Importantly, because there are known sex differences in cerebral blood flow physiology and response to SCI, we will examine the hemodynamic changes that occur after cervical SCI in both males and females. By applying this innovative ultrasound imaging approach, we aim to (1) monitor the spatial and temporal development of intraparenchymal hypoperfusion in adult, middle- aged and aged rats, (2) discover perilesional hemodynamic characteristics for vulnerable tissue, and (3) evaluate treatment effects (i.e., vasopressors) that are thought to improve local microvascular flow in real-time. Overall, these studies will provide direct insights into the contribution of the acute microvascular response to trauma in the aged spinal cord that directly impacts functional recovery after SCI.