Abstract
Stromal cell-derived factor 1 (SDF-1) and its main receptor, CXC chemokine receptor 4 (CXCR4), play a critical role in endothelial cell function regulation during cardiogenesis, angiogenesis, and reendothelialization after injury. The expression of CXCR4 and SDF-1 in brain endothelial cells decreases due to ionizing radiation treatment and aging. SDF-1 protein treatment in the senescent and radiation-damaged cells reduced several senescence phenotypes, such as decreased cell proliferation, upregulated p53 and p21 expression, and increased senescence-associated beta-galactosidase (SA-β-gal) activity, through CXCR4-dependent signaling. By inhibiting extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription protein 3 (STAT3), we confirmed that activation of both is important in recovery by SDF-1-related mechanisms. A CXCR4 agonist, ATI2341, protected brain endothelial cells from radiation-induced damage. In irradiation-damaged tissue, ATI2341 treatment inhibited cell death in the villi of the small intestine and decreased SA-β-gal activity in arterial tissue. An ischemic injury experiment revealed no decrease in blood flow by irradiation in ATI2341-administrated mice. ATI2341 treatment specifically affected CXCR4 action in mouse brain vessels and partially restored normal cognitive ability in irradiated mice. These results demonstrate that SDF-1 and ATI2341 may offer potential therapeutic approaches to recover tissues damaged during chemotherapy or radiotherapy, particularly by protecting vascular endothelial cells.
Highlights
With an increase in the worldwide elderly population, there is an increasing awareness of age-related impairments in cognitive function that present significant individual and socioeconomic impacts
To determine whether CXC chemokine receptor 4 (CXCR4) and stromal cell-derived factor 1 (SDF-1) expression were altered with ionizing radiation (IR) treatment, expression was confirmed by dose- and time-dependent radiation changes in Human brain microvascular endothelial cells (HBMVECs)
These results demonstrate that CXCR4 and SDF-1 expression is involved in cellular senescence and radiation-induced damage in brain endothelial cells
Summary
With an increase in the worldwide elderly population, there is an increasing awareness of age-related impairments in cognitive function that present significant individual and socioeconomic impacts. Recent studies suggest that radiation exposure, even at low doses, could trigger cognitive dysfunctions seen in normal aging and lead to the development of Alzheimer’s disease [1,2]. Central nervous system aging and diverse triggers of neurodegenerative processes are still the focus of cognitive decline and disease studies and treatments, Cells 2019, 8, 1230; doi:10.3390/cells8101230 www.mdpi.com/journal/cells. Endothelial cell loss causes blood vessel leakage that can lead to cognitive decline [6,7]. Since cerebromicrovascular endothelial cells are a key component of the blood–brain barrier, damage to capillaries, especially in the cerebral cortex and hippocampus, causes regional cerebral blood flow decreases, reduced cerebral glucose utilization, the loss of vascular innervation, and eventually cognitive failure [5,8,9,10]
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