Different cyclical intermittent hypoxia severities have different effects on hippocampal microvasculature

Abstract

Recent studies have shown an association between obstructive sleep apnea (OSA) and cognitive impairment. This study was done to investigate whether varied levels of cyclical intermittent hypoxia (CIH) differentially affect the microvasculature in the hippocampus, operating as a mechanistic link between OSA and cognitive impairment. We exposed C57BL/6 mice to sham [continuous air, arterial O2 saturation (SaO2 ) 97%], severe CIH to inspired O2 fraction (FiO2 ) = 0.10 (CIH10; SaO2 nadir of 61%), or very severe CIH to FiO2 = 0.05 (CIH5; SaO2 nadir of 37%) for 12 h/day for 2 wk. We quantified capillary length using neurostereology techniques in the dorsal hippocampus and utilized quantitative PCR methods to measure changes in sets of genes related to angiogenesis and to metabolism. Next, we employed immunohistochemistry semiquantification algorithms to quantitate GLUT1 protein on endothelial cells within hippocampal capillaries. Capillary length differed among CIH severity groups (P = 0.013) and demonstrated a linear relationship with CIH severity (P = 0.002). There was a strong association between CIH severity and changes in mRNA for VEGFA (P < 0.0001). Less strong, but nominally significant associations with CIH severity were also observed for ANGPT2 (PANOVA = 0.065, PTREND = 0.040), VEGFR2 (PANOVA = 0.032, PTREND = 0.429), and TIE-2 (PANOVA = 0.006, PTREND = 0.010). We found that the CIH5 group had increased GLUT1 protein relative to sham (P = 0.006) and CIH10 (P = 0.001). There was variation in GLUT1 protein along the microvasculature in different hippocampal subregions. An effect of CIH5 on GLUT1 mRNA was seen (PANOVA = 0.042, PTREND = 0.012). Thus CIH affects the microvasculature in the hippocampus, but consequences depend on CIH severity.

Intermittent Hypoxia Severity in Animal Models of Sleep Apnea

“…To realistically model intermittent hypoxemia in OSA it is important to bear in mind that the potential effect of this exposure depends on the magnitude of the decrease in arterial oxygen partial pressure (PaO 2 ), since this biological variable de facto determines the PO 2 gradient across the capillary membrane, and hence oxygen delivery to cells within the various tissues. In practice, the conventional setting for subjecting animals to intermittent hypoxia consists of cyclically changing the oxygen fraction (FiO 2 ) in the environmental gas breathed by the animals from room air (F I O 2 - 21%) to different nadir values ranging from F I O 2 of 4 to 15%, and thus model different degrees of hypoxia severity which, as would be anticipated, yield dose-response effects (Nagai et al, 2014 ; Lim et al, 2016 ; Gallego-Martin et al, 2017 ; Docio et al, 2018 ). When using this experimental setting the degree of intermittent hypoxemia achieved for a given FiO 2 swing is similar in young and old animals (Dalmases et al, 2014 ) which is interesting given that the effects of hypoxia/reoxygenation are modulated by age (Torres et al, 2018 ).…”

“…The major controversial point refers to one of the most commonly employed paradigms of intermittent hypoxia when applied to mice, and resulting in measured SaO 2 swings with nadir values in the range 50–70% (Jun et al, 2010 ; Reinke et al, 2011 ; Torres et al, 2014 , 2015 ; Lim et al, 2015 , 2016 ). Specifically, in a recent review focused on sleep apnea research in animals, it was stated that such intermittent hypoxia profiles may result in significantly more severe hypoxic events than those typically experienced by patients with OSA, in whom SaO 2 nadir ranges of 77–90% are usually documented (Lim et al, 2015 ), and that therefore extrapolation from murine models to human disease should be applied with caution (Chopra et al, 2016 ).…”

Ischaemic and hypoxic conditioning: potential for protection of vital organs

“…Hypoxia exposures 14–15 h after OGD prevented death of embryonic mouse neurons, while an inhibitor of HIF‐1 DNA binding blocked the protection (Leconte et al., ). IHT activated HIF‐1‐driven expression of GLUT1 glucose transporters (Kalaria et al., ; Lim et al., ), increasing the capacity for glucose delivery to the brain parenchyma. HIF‐1 also augments glycolytic enzymes (Brix, Mesters, Pellerin, & Johren, ; Ryou et al., ), pro‐angiogenic vascular endothelial growth factor (VEGF) (Ran, Xu, Lu, Bernaudin, & Sharp, ) and a powerful cytoprotectant, erythropoietin (EPO) (Zhu et al., ).…”

Circulating exosomes in obstructive sleep apnea as phenotypic biomarkers and mechanistic messengers of end-organ morbidity

“…We are unaware of any published work on the impact of IH on exosome release and their biological properties in the CNS. Considering the extensive evidence indicating substantial structural and functional changes induced by chronic IH in brain regions cognitive, behavioral, mood, and autonomic functions (Burckhardt et al, 2008; Capone et al, 2012; Cheng et al, 2011; Darnall et al, 2017; Dayyat et al, 2012; Douglas et al, 2010; Goldbart et al, 2003; Gozal et al, 2001; Kanaan et al, 2006; Kim et al, 2015; Knight et al, 2011; Li et al, 2004; Lim et al, 2016; Nair et al, 2011; Row et al, 2007; Sapin et al, 2015; Shan et al, 2007; Xu et al, 2015; Xu et al, 2004; Yagishita et al, 2017; Zhan et al, 2005), it would be important to explore the potential contributions of exosomes in these contextual settings both as biomarkers for CNS morbidity as well as novel therapeutic targets. In addition, circulating EVs/exosomes have been associated with various diseases severity.…”