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.
Highlights
Sleep is a fundamental physiological function involved in the restoration of cellular and organ homeostasis and is essential for optimal daytime functioning
We examined brain hCMEC/D3 cells, which constitute the endothelial cells of the blood–brain barrier (BBB), as well as several other endothelial cells such as skin HMVEC-d, coronary artery Human coronary artery endothelial cells (HCAEC), iliac artery HIAEC, cardiac ventricles HMVEC-C, and lung human lung microvascular endothelial cells (HMVEC-L)
We showed that circulating plasma extracellular vesicles (EVs) derived from children with OSA in the presence or absence of cognitive deficits disrupt the integrity of the BBB with such effects being prominent among the children with cognitive deficits
Summary
Sleep is a fundamental physiological function involved in the restoration of cellular and organ homeostasis and is essential for optimal daytime functioning. Restricted or poor-quality sleep has been associated with neurobehavioral and cognitive deficits, end-organ dysfunction, and chronic health conditions [1,2,3,4,5,6]. Differentiated endothelial cells line the walls of the brain capillaries and serve as the primary constitutive elements of the BBB, with the combined surface area of these capillaries forming the major interface for blood–brain exchange [18,20]. Impairments of the endothelial barrier function have been linked to a variety of disease states, and OSA is clearly one of such conditions in which the endothelium emerges as a target organ [21,22,23]. Identification of biomarkers and of specific endothelia cell selectivity in children with neurocognitive impairments would potentially provide mechanistic insights and therapeutic targets
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