title: 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.
authors.affiliation: Division of Sleep Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania; limdiane@mail.med.upenn.edu.
authors.forename: Diane C
authors.identifier: 0000-0001-5748-629X
authors.initials: DC
authors.lastname: Lim
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Brady
authors.affiliation: Department of Electrical and Computer Engineering, Drexel University, Philadelphia, Pennsylvania;
authors.forename: Rajath
authors.initials: R
authors.lastname: Soans
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Superior School of Health Sciences, Brasilia, Brazil; and.
authors.forename: Laise
authors.initials: L
authors.lastname: Valverde
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Keenan
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Guo
authors.affiliation: Korea University, Seoul, Korea.
authors.forename: Woo Young
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Korea University, Seoul, Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Raymond
authors.initials: R
authors.lastname: Galante
authors.affiliation: Department of Electrical and Computer Engineering, Drexel University, Philadelphia, Pennsylvania;
authors.forename: James A
authors.initials: JA
authors.lastname: Shackleford
authors.affiliation: Division of Sleep Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Allan I
authors.initials: AI
authors.lastname: Pack
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000378:metabolism / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D051272:Glucose Transporter Type 1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: GLUT1 transporter; VEGF; angiogenesis; blood-brain barrier; cyclical intermittent hypoxia; obstructive sleep apnea; vascular endothelium