Characterising vascular changes in the spinal cord after injury as a novel therapeutic target

After spinal cord injury (SCI), vascular integrity is disrupted by the primary mechanical trauma and secondary biochemical insult, impeding neuronal regeneration and functional recovery. A systematic analysis of changes within the capillary bed following common angiogenic treatments in rats before and after moderate/severe T10 contusion injury aimed to identify potential targets for vascular regeneration. A combined intrathecal delivery of angiopoeitin-1 (Ang1) and vascular endothelial growth factor (VEGF) may stabilise damaged microvessels and promote angiogenesis. Intact rats received prazosin administration or wheel running for 10 days before perfuse fixation. Animals with an SCI were perfuse-fixed on days 2, 5, 15, and 45 post-injury. A parallel group of animals also had a subdural osmotic pump inserted delivering Ang1/VEGF or a vehicle intrathecally for 14 days, and were perfuse-fixed at days 5 and 15. Capillary number, surface area, areal density, and feret diameter were measured. Transmission electron microscopy (TEM) was used to characterise vessel microstructure. Accurate and reliable capillary staining was optimised, however no angiogenesis was observed in intact spinal cords following angiogenic stimuli. Adverse, widespread changes in injured spinal vasculature showed some recovery with time. Capillary collapse close to the injury epicentre partially resolved by day 15, however vessel abnormalities were present at day 45. TEM confirmed severe vessel damage at day 2; endothelial cell tight junction structure was significantly compromised. Ang1/VEGF delivery led to improved vascular morphology compared to vehicle controls, particularly at T11. However, TEM measurements were variable following Ang1/VEGF treatment between regions and timepoints, potentially indicating the balance of Ang1/VEGF needs optimising. These studies demonstrated acute regression or collapse of capillaries after SCI, with abnormal vessels persisting for at least 45 days. Stabilising the capillaries and promoting angiogenesis using Ang1 and VEGF respectively showed promise as an approach to reduce this damage and potentially encourage functional recovery after SCI.