title: Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells.
abstract: Whole brain radiation therapy (WBRT) induces profound cerebral microvascular rarefaction throughout the hippocampus. Despite the vascular loss and localized cerebral hypoxia, angiogenesis fails to occur, which subsequently induces long-term deficits in learning and memory. The mechanisms underlying the absence of vessel recovery after WBRT are unknown. We tested the hypotheses that vascular recovery fails to occur under control conditions as a result of loss of angiogenic drive in the circulation, chronic tissue inflammation, and/or impaired endothelial cell production/recruitment. We also tested whether systemic hypoxia, which is known to promote vascular recovery, reverses these chronic changes in inflammation and endothelial cell production/recruitment. Ten-week-old C57BL/6 mice were subjected to a clinical series of fractionated WBRT: 4.5-Gy fractions 2 times/wk for 4 wk. Plasma from radiated mice increased in vitro endothelial cell proliferation and adhesion compared with plasma from control mice, indicating that WBRT did not suppress the proangiogenic drive. Analysis of cytokine levels within the hippocampus revealed that IL-10 and IL-12(p40) were significantly increased 1 mo after WBRT; however, systemic hypoxia did not reduce these inflammatory markers. Enumeration of endothelial progenitor cells (EPCs) in the bone marrow and circulation indicated that WBRT reduced EPC production, which was restored with systemic hypoxia. Furthermore, using a bone marrow transplantation model, we determined that bone marrow-derived endothelial-like cells home to the hippocampus after systemic hypoxia. Thus, the loss of production and homing of EPCs have an important role in the prolonged vascular rarefaction after WBRT.
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Ashpole
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Junie P
authors.initials: JP
authors.lastname: Warrington
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Mitschelen
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Julie A
authors.initials: JA
authors.lastname: Farley
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and william-sonntag@ouhsc.edu.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001930:Brain Injuries / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019583:Dose Fractionation, Radiation; D042783:Endothelial Cells / Q000473:pathology / Q000528:radiation effects* / Q000637:transplantation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply* / Q000473:pathology / Q000528:radiation effects*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D018919:Neovascularization, Physiologic / Q000528:radiation effects*; D011832:Radiation Injuries / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D055153:Stem Cell Niche; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors; D014916:Whole-Body Irradiation
chemical_list: C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D016753:Interleukin-10; D049452:Green Fluorescent Proteins
keywords: angiogenesis; cytokines; endothelial progenitor cells; hypoxia; radiation therapy