Systemic hypoxia reverses whole brain radiation‐induced microvascular rarefaction

Whole brain radiation therapy (WBRT) leads to cognitive deficits in 40–50% of brain tumor survivors following treatment. Although the etiology of cognitive deficits post‐WBRT is unclear, vascular rarefaction appears to be an important contributing factor. In this study, we assessed whether WBRT produces hippocampal microvascular rarefaction and whether chronic hypoxia can reverse capillary loss. Transgenic mice expressing GFP driven by Acta2 (smooth muscle actin) promoter for blood vessel visualization, were randomly assigned to control or radiated groups. Animals received a clinical series of 4.5Gy WBRT twice weekly for 4 weeks. One month post‐treatment, learning and memory were assessed. Subsequently, mice were subjected to 11% (hypoxia) or 21% oxygen (normoxia) for 1 month. Profound cognitive deficits and capillary rarefaction were evident in radiated animals despite hypoxia in brain (increased levels of HIF‐1α and VEGF‐R2 protein). Nevertheless, systemic hypoxia completely restored capillary density to that of controls. We conclude that WBRT‐induced hippocampal capillary rarefaction: 1) is a contributing factor in cognitive impairment, 2) is not adequate to stimulate angiogenesis, and 3) can be reversed by systemic hypoxia. Our data support the hypothesis that WBRT impairs local angiogenic pathways but vasculogenesis remains intact and is able to re‐establish cerebral capillary density. Funding: NIH Grant: NS056218 and AG11370 (WES); American Heart Association Pre‐doctoral Fellowship (JPW); GSA Research Grant (JPW)