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Whole Brain Irradiation Impairs Cerebromicrovascular Function and Promotes Cognitive Decline: Potential Role of Endothelial Senescence
Author(s) -
Yabluchanskiy Andriy,
Hertelendy Peter,
Ashpole Nicole M,
Tarantini Stefano,
Logan Sreemathi,
Owen Daniel B,
Farley Julie A,
Ungvari Zoltan,
Sonntag William E,
Csiszar Anna
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.728.2
Subject(s) - senescence , cognitive decline , medicine , cd31 , neurovascular bundle , endocrinology , pathology , immunohistochemistry , dementia , disease
Whole brain irradiation (WBI) leads to a progressive cognitive dysfunction in up to 50% of tumor patients surviving long‐term after treatment, due to, at least in part, γ‐irradiation induced cerebromicrovascular injury. Moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has a critical role in maintenance of healthy cognitive function. To determine whether cognitive decline induced by WBI associates with cerebrovascular dysfunction and neurovascular un‐coupling, C56BL/6J mice (3 mo) subjected to fractionated WBI (5Gy twice weekly for 4 weeks) and control mice were compared. Mice were tested for spatial memory performance (radial arm water maze), neurovascular coupling, endothelial function, and were sacrificed for molecular and immunohistochemical (IHC) analyses 90 days post‐irradiation. Mice with WBI showed impaired performance in the radial arm maze (increased path length vs control; p<0.05). WBI significantly decreased endothelium‐mediated CBF responses (laser Doppler flowmetry) in the somatosensory cortex evoked by contralateral whisker stimulation. In cultured cerebromicrovascular endothelial cells, γ‐irradiation induced replicative senescence and acquisition of a senescence‐associated secretory phenotype (SASP). In the mouse brain, WBI resulted in up‐regulation of the senescence‐associated genes, including Cdkn2a (p16 INK4a ), Serpine1 (PAI‐1), and the SASP genes Mcp2 , IL6 , IL1b (qPCR) . IHC analysis revealed that the DNA damage marker H2AX was co‐localized with CD31 positive cells in sections from WBI mice. Collectively, our findings provide evidence for persistent neurovascular un‐coupling, highlighting the potential role of endothelial senescence in cerebromicrovascular dysfunction and cognitive decline induced by WBI. Support or Funding Information This study is supported by the Donald W. Reynolds Foundation and NINDS grant NS056218‐08 to WES.