Vascular Cell Senescence Contributes to Blood–Brain Barrier Breakdown

Abstract

Background and Purpose Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Since the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to age-related organ dysfunction, we evaluated whether senescent vascular cells are associated with compromised BBB integrity. Methods Effects of vascular cell senescence on tight junction (TJ) and barrier integrity were studied using an in vitro BBB model, composed of endothelial cells (ECs), pericytes (PCs) and astrocytes. Additionally, TJ coverage in microvessels and BBB integrity in BubR1 hypomorphic (BubR1H/H) mice, which display senescence cell-dependent phenotypes, were examined. Results When an in vitro BBB model was constructed with senescent ECs and PCs, TJ structure and barrier integrity (evaluated by transendothelial electrical resistance and tracer efflux assay using sodium fluorescein (NaF) and Evans blue (EB)-albumin) were significantly impaired. ECs and PCs from BubR1H/H mice had increased SA-β-gal activity and p16INK4a expression, demonstrating an exacerbation of senescence. The coverage by TJ proteins in the cortical microvessels were reduced in BubR1H/H mice, consistent with a compromised BBB integrity from permeability assays. Importantly, the coverage of microvessels by end-feet of aquaporin 4 (AQP4)-immunoreactive astrocytes was not altered in the cortex of the BubR1H/H mice. Conclusions Our results indicate that accumulation of senescent vascular cells is associated with compromised BBB integrity, providing insights into the mechanism of BBB disruption related to biological aging.

Differential Expression of CD31 and Von Willebrand Factor on Endothelial Cells in Different Regions of the Human Brain: Potential Implications for Cerebral Malaria Pathogenesis

“…This notwithstanding, age-associated microvascular changes have been implicated in Alzheimer's disease (AD) and vascular dementia [26]. These changes have been suggested to influence the nature and function of the BBB [27,28]. They include loss of junctional complexes, inflammation, cellular damage, and vascular remodeling [29].…”

Endothelial toll‐like receptor 4 maintains lung integrity via epigenetic suppression of p16INK4a

“…Cellular senescence, an irreversible cell cycle process, acts to protect against cancer, and more recently, this process is emerging as a regulator of complex biological processes such as development, tissue repair, and aging (van Deursen, ). For instance, ablation of p16 INK4a reverses the aging phenotype in α‐klotho, an aging suppressor gene, knockout mice (Sato et al, ), and brain Ec are reported as a susceptible cell type in BubR1 hypomorphic‐induced premature senescence mice, confirmed by increased SA‐β‐gal activity and p16 INK4a expression (Yamazaki et al, ). Recently, Baker et al () showed that p16 INK4a positive cells promote age‐dependent changes in organs such as kidney, heart, and fat, but notably these studies excluded lungs.…”

The blood-brain interface: a culture change

“…Chronic inflammation and increased EC turnover leads to EC replicative senescence, a cellular state defined by cell cycle arrest (Hornsby, 2010). Accumulation of senescent ECs is associated with disrupted TJs and increased permeability in vitro and in vivo (Yamazaki et al, 2016). Senescent cells typically have a senescence-associated secretory phenotype (SASP), during which production of pro-inflammatory molecules stimulate leukocyte migration, activation and infiltration (Lasry and Ben-Neriah, 2015).…”