title: Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity.
abstract: Cerebromicrovascular rarefaction is believed to play a central role in cognitive impairment in patients receiving whole-brain irradiation therapy. To elucidate the mechanism underlying the deleterious effects of γ-irradiation on the cerebral microcirculation, rat primary cerebromicrovascular endothelial cells (CMVECs) were irradiated in vitro. We found that in CMVECs, γ-irradiation (2-8 Gy) elicited increased DNA damage, which was repaired less efficiently in CMVECs compared with neurons, microglia, and astrocytes. Increased genomic injury in CMVECs associated with increased apoptotic cell death. In the surviving cells, γ-irradiation promotes premature senescence (indicated by SA-β-galactosidase positivity and upregulation of p16 (INK4a) ), which was associated with impaired angiogenic capacity (decreased proliferation and tube-forming capacity). γ-Irradiated CMVECs acquired a senescence-associated secretory phenotype, characterized by upregulation of proinflammatory cytokines and chemokines (including IL-6, IL-1α, and MCP-1). Collectively, increased vulnerability of γ-irradiated CMVECs and their impaired angiogenic capacity likely contribute to cerebromicrovascular rarefaction and prevent regeneration of the microvasculature postirradiation. The acquisition of a senescence-associated secretory phenotype in irradiated CMVECs is biologically highly significant as changes in the cytokine microenvironment in the hippocampus may affect diverse biological processes relevant for normal neuronal function (including regulation of neurogenesis and the maintenance of the blood brain barrier).
authors.affiliation: *These authors contributed equally to this work.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.forename: Andrej
authors.initials: A
authors.lastname: Podlutsky
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.forename: Ferenc
authors.initials: F
authors.lastname: Deak
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002468:Cell Physiological Phenomena / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D015140:Dementia, Vascular / Q000209:etiology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects*; D019942:Genes, p16 / Q000528:radiation effects; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D055806:Microvessels / Q000378:metabolism / Q000528:radiation effects; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000528:radiation effects; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000528:radiation effects; D051381:Rats; D055571:Secretory Pathway / Q000235:genetics / Q000528:radiation effects; D015854:Up-Regulation / Q000235:genetics / Q000528:radiation effects; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D016207:Cytokines; D001616:beta-Galactosidase
keywords: Angiogenesis; Capillary.; Endothelial; Inflammation; Oxidative stress; Senescence; Vascular cognitive impairment