Age-related phenotypic changes of cerebromicrovascular endothelial cells lead to dysregulation
of cerebral blood flow and blood-brain barrier disruption, promoting the pathogenesis
of vascular cognitive impairment (VCI). In recent years, endothelial cell senescence
has emerged as a potential mechanism contributing to microvascular pathologies opening
the avenue to the therapeutic exploitation of senolytic drugs in preclinical studies.
However, difficulties with the detection of senescent endothelial cells in wild type
mouse models of aging hinder the assessment of the efficiency of senolytic treatments.
To detect senescent endothelial cells in the aging mouse brain, we analyzed 4233 cells
in fractions enriched for cerebromicrovascular endothelial cells and other cells associated
with the neurovascular unit obtained from young (3-month-old) and aged (28-month-old)
C57BL/6 mice. We define 13 transcriptomic cell types by deep, single-cell RNA sequencing.
We match transcriptomic signatures of cellular senescence to endothelial cells identified
on the basis of their gene expression profile. Our study demonstrates that with advanced
aging, there is an increased ratio of senescent endothelial cells (similar to 10%)
in the mouse cerebral microcirculation. We propose that our single-cell RNA sequencing-based
method can be adapted to study the effect of aging on senescence in various brain
cell types as well as to evaluate the efficiency of various senolytic regimens in
multiple tissues.
