Plasma Extracellular Vesicles in Children with OSA Disrupt Blood–Brain Barrier Integrity and Endothelial Cell Wound Healing In Vitro

Abstract

Pediatric obstructive sleep apnea (P-OSA) is associated with neurocognitive deficits and endothelial dysfunction, suggesting the possibility that disruption of the blood–brain barrier (BBB) may underlie these morbidities. Extracellular vesicles (EVs), which include exosomes, are small particles involved in cell–cell communications via different mechanisms and could play a role in OSA-associated end-organ injury. To examine the roles of EVs in BBB dysfunction, we recruited three groups of children: (a) absence of OSA or cognitive deficits (CL, n = 6), (b) OSA but no evidence of cognitive deficits (OSA-NC(−), n = 12), and (c) OSA with evidence of neurocognitive deficits (OSA-NC(+), n = 12). All children were age-, gender-, ethnicity-, and BMI-z-score-matched, and those with OSA were also apnea–hypopnea index (AHI)-matched. Plasma EVs were characterized, quantified, and applied on multiple endothelial cell types (HCAEC, HIAEC, human HMVEC-D, HMVEC-C, HMVEC-L, and hCMEC/D3) while measuring monolayer barrier integrity and wound-healing responses. EVs from OSA children induced significant declines in hCMEC/D3 transendothelial impedance compared to CL (p < 0.001), and such changes were greater in NC(+) compared to NC(−) (p < 0.01). The effects of EVs from each group on wound healing for HCAEC, HIAEC, HMVED-d, and hCMEC/D3 cells were similar, but exhibited significant differences across the three groups, with evidence of disrupted wound healing in P-OSA. However, wound healing in HMVEC-C was only affected by NC(+) (p < 0.01 vs. NC(−) or controls (CO). Furthermore, no significant differences emerged in HMVEC-L cell wound healing across all three groups. We conclude that circulating plasma EVs in P-OSA disrupt the integrity of the BBB and exert adverse effects on endothelial wound healing, particularly among OSA-NC(+) children, while also exhibiting endothelial cell type selectivity. Thus, circulating EVs cargo may play important roles in the emergence of end-organ morbidity in pediatric OSA.

Leakage of astrocyte-derived extracellular vesicles in stress-induced exhaustion disorder: a cross-sectional study

“…The cellular changes cause the formation and release of EVs, which could pass through the BBB and be detectable in the blood. The stimuli could be stress hormones, cytokines as part of inflammatory processes, and/or EVs from peripheral blood 32 . A study of children with obstructive sleep apnea found that EVs in peripheral blood disrupted the integrity of the BBB, especially in those with neurocognitive deficits 32 .…”

“…The stimuli could be stress hormones, cytokines as part of inflammatory processes, and/or EVs from peripheral blood 32 . A study of children with obstructive sleep apnea found that EVs in peripheral blood disrupted the integrity of the BBB, especially in those with neurocognitive deficits 32 . Further studies are needed to better understand the processes that allow release of astrocyte-derived EVs from the CNS into peripheral blood after exposure to stress and the clinical relevance of this.…”

Sera of elderly obstructive sleep apnea patients alter blood–brain barrier integrity in vitro: a pilot study

“…However, such pro-inflammatory interleukin activation is not constant in OSAS patients and more particularly in adults and in the elderly. Furthermore, microparticles described in OSAS sera patients could lead by themselves to endothelial dysfunction at the brain vascular scale and could alter BBB permeability, like as found in an exosome 46,47 . Indeed, serum factors are not yet identified, and inflammation remains a hypothesis.…”

Validity and Cost-Effectiveness of Pediatric Home Respiratory Polygraphy for the Diagnosis of Obstructive Sleep Apnea in Children: Rationale, Study Design, and Methodology

“…Morning first void mid-stream urine samples will be collected after each of the two PSG in two 50 mL aliquots that will be immediately stored at −70 degrees until their analysis in the laboratory of the Department of Child Health at the University of Missouri School of Medicine at Columbia, MO, USA. After appropriate aliquoting and initial centrifugation and vortexing, isolation of exosomes will be performed as previously reported [ 66 , 67 ]. Circulating miRNAs are in body fluids such as in urine and are packaged in secreted urinary extracellular vesicles which protect them from degradation.…”