title: Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice.
abstract: Whole brain radiation therapy (WBRT) leads to cognitive impairment in 40-50% of brain tumor survivors following treatment. Although the etiology of cognitive deficits post-WBRT remains unclear, vascular rarefaction appears to be an important component of these impairments. In this study, we assessed the effects of WBRT on the cerebrovasculature and the effects of systemic hypoxia as a potential mechanism to reverse the microvascular rarefaction. Transgenic mice expressing green fluorescent protein driven by the Acta2 (smooth muscle actin) promoter for blood vessel visualization were randomly assigned to control or radiated groups. Animals received a clinical series of 4.5 Gy WBRT two times weekly for 4 wk followed by 1 mo of recovery. Subsequently, mice were subjected to 11% (hypoxia) or 21% (normoxia) oxygen for 1 mo. Capillary density in subregions of the hippocampus revealed profound vascular rarefaction that persisted despite local tissue hypoxia. Nevertheless, systemic hypoxia was capable of completely restoring cerebrovascular density. Thus hippocampal microvascular rarefaction post-WBRT is not capable of stimulating angiogenesis and can be reversed by chronic systemic hypoxia. Our results indicate a potential shift in sensitivity to angiogenic stimuli and/or the existence of an independent pathway of regulating cerebral microvasculature.
authors.affiliation: Oklahoma Center for Neuroscience, Oklahoma Center on Aging, Donald W Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. william-sonntag@ouhsc.edu
authors.forename: Junie P
authors.initials: JP
authors.lastname: Warrington
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Terence S
authors.initials: TS
authors.lastname: Herman
authors.forename: Salahuddin
authors.initials: S
authors.lastname: Ahmad
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Lee
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000693:Anaerobiosis; D000818:Animals; D003071:Cognition / Q000502:physiology / Q000528:radiation effects*; D003072:Cognition Disorders / Q000503:physiopathology* / Q000628:therapy*; D006624:Hippocampus / Q000098:blood supply* / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000503:physiopathology / Q000528:radiation effects; D010100:Oxygen / Q000502:physiology*; D011401:Promoter Regions, Genetic
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D010100:Oxygen