Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury

Mild traumatic brain injury (mTBI) is a common and unmet clinical issue, with limited treatments available to improve recovery. The cerebrovascular system is vital to provide oxygen and nutrition to the brain, and a growing body of research indicates that cerebrovascular injury contributes to mTBI symptomatology. Vascular endothelial growth factor-A (VEGF-A) is a potent promoter of angiogenesis and an important modulator of vascular health. While indirect evidence suggests that increased bioavailability of VEGF-A may be beneficial after mTBI, the direct therapeutic effects of VEGF-A in this context remains unknown. This study therefore aimed to determine whether intracerebroventricular administration of recombinant VEGF-A could improve recovery from mTBI in a rat model. Male and female Sprague–Dawley rats were assigned to four groups: sham + vehicle (VEH), sham + VEGF-A, mTBI + VEH, mTBI + VEGF-A. The mTBI was induced using the lateral impact model, and treatment began at the time of the injury and continued until the end of the study. Rats underwent behavioral testing between days 1 and 10 post-injury, and were euthanized on day 11 for post-mortem analysis. In males, the mTBI + VEGF-A group had significantly worse cognitive recovery in the water maze than all other groups. In females, the VEGF treatment worsened cognitive performance in the water maze regardless of mTBI or sham injury. Analysis of hippocampal tissue found that these cognitive deficits occurred in the presence of gene expression changes related to neuroinflammation and hypoxia in both male and female rats. These findings indicate that the VEGF-A treatment paradigm tested in this study failed to improve mTBI outcomes in either male or female rats.