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

Zoltan Ungvari, Andrej Podlutsky, Danuta Sosnowska, Zsuzsanna Tucsek, Peter Toth, Ferenc Deak, Tripti Gautam, Anna Csiszar, William E. Sonntag

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Cerebromicrovascular rarefaction is believed to play a central role in cognitive impairment in patients receiving wholebrain irradiation therapy. To elucidate the mechanism underlying the deleterious effects of ?-irradiation on the cerebral microcirculation, rat primary cerebromicrovascular endothelial cells (CMVECs) were irradiated in vitro. We found that in CMVECs, ?-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, ?-irradiation promotes premature senescence (indicated by SA-?-galactosidase positivity and upregulation of p16INK4a), which was associated with impaired angiogenic capacity (decreased proliferation and tube-forming capacity). ?-Irradiated CMVECs acquired a senescence-associated secretory phenotype, characterized by upregulation of proinflammatory cytokines and chemokines (including IL-6, IL-1?, and MCP-1). Collectively, increased vulnerability of ?-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).

Original languageEnglish (US)
Pages (from-to)1443-1457
Number of pages15
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume68
Issue number12 A
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • Angiogenesis
  • Capillary
  • Endothelial
  • Inflammation
  • Oxidative stress
  • Senescence
  • Vascular cognitive impairment

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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