Different cyclical intermittent hypoxia severities have different effects on hippocampal microvasculature
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 betw...
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creator | Lim, Diane C Brady, Daniel C Soans, Rajath Kim, Emily Y Valverde, Laise Keenan, Brendan T Guo, Xiaofeng Kim, Woo Young Park, Min Jeong Galante, Raymond Shackleford, James A Pack, Allan I |
description | 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. |
doi_str_mv | 10.1152/japplphysiol.01040.2015 |
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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.</description><identifier>ISSN: 8750-7587</identifier><identifier>EISSN: 1522-1601</identifier><identifier>DOI: 10.1152/japplphysiol.01040.2015</identifier><identifier>PMID: 27125850</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Angiogenesis ; Angiopoietin-2 - metabolism ; Animals ; Capillaries - metabolism ; Capillaries - physiopathology ; Cognitive ability ; Disease Models, Animal ; Glucose Transporter Type 1 - metabolism ; Hippocampus - metabolism ; Hippocampus - physiopathology ; Hypoxia ; Hypoxia - metabolism ; Hypoxia - physiopathology ; Male ; Metabolism ; Mice ; Mice, Inbred C57BL ; Microvessels - metabolism ; Microvessels - physiopathology ; Physiology ; Receptor, TIE-2 - metabolism ; RNA, Messenger - metabolism ; Sleep apnea ; Sleep Apnea, Obstructive - metabolism ; Sleep Apnea, Obstructive - physiopathology ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor Receptor-2 - metabolism</subject><ispartof>Journal of applied physiology (1985), 2016-07, Vol.121 (1), p.78-88</ispartof><rights>Copyright © 2016 the American Physiological Society.</rights><rights>Copyright American Physiological Society Jul 1, 2016</rights><rights>Copyright © 2016 the American Physiological Society 2016 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-a7bdbf2cf1eebd688c5c043eb3791e95765e291bf87175ba8a3f787f55b7d4ac3</citedby><orcidid>0000-0001-5748-629X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3039,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27125850$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lim, Diane C</creatorcontrib><creatorcontrib>Brady, Daniel C</creatorcontrib><creatorcontrib>Soans, Rajath</creatorcontrib><creatorcontrib>Kim, Emily Y</creatorcontrib><creatorcontrib>Valverde, Laise</creatorcontrib><creatorcontrib>Keenan, Brendan T</creatorcontrib><creatorcontrib>Guo, Xiaofeng</creatorcontrib><creatorcontrib>Kim, Woo Young</creatorcontrib><creatorcontrib>Park, Min Jeong</creatorcontrib><creatorcontrib>Galante, Raymond</creatorcontrib><creatorcontrib>Shackleford, James A</creatorcontrib><creatorcontrib>Pack, Allan I</creatorcontrib><title>Different cyclical intermittent hypoxia severities have different effects on hippocampal microvasculature</title><title>Journal of applied physiology (1985)</title><addtitle>J Appl Physiol (1985)</addtitle><description>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.</description><subject>Angiogenesis</subject><subject>Angiopoietin-2 - metabolism</subject><subject>Animals</subject><subject>Capillaries - metabolism</subject><subject>Capillaries - physiopathology</subject><subject>Cognitive ability</subject><subject>Disease Models, Animal</subject><subject>Glucose Transporter Type 1 - metabolism</subject><subject>Hippocampus - metabolism</subject><subject>Hippocampus - physiopathology</subject><subject>Hypoxia</subject><subject>Hypoxia - metabolism</subject><subject>Hypoxia - physiopathology</subject><subject>Male</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microvessels - metabolism</subject><subject>Microvessels - physiopathology</subject><subject>Physiology</subject><subject>Receptor, TIE-2 - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>Sleep apnea</subject><subject>Sleep Apnea, Obstructive - metabolism</subject><subject>Sleep Apnea, Obstructive - physiopathology</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - metabolism</subject><issn>8750-7587</issn><issn>1522-1601</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFv1DAQhS0EokvhL0AkLr1k8Th27FyQUGkBqVIv5Ww5zoR45cTBTlbsv8fbllXhxMmW53tP4_cIeQd0CyDYh52ZZz8Ph-SC31KgnG4ZBfGMbPKUlVBTeE42SgpaSqHkGXmV0o5S4FzAS3LGJDChBN0Q99n1PUaclsIerHfW-MJNC8bRLcvxdTjM4ZczRcI9Rrc4TMVg9lh0Jx3mi11SEaZicPMcrBnn7DI6G8PeJLt6s6wRX5MXvfEJ3zye5-T79dXd5dfy5vbLt8tPN6XlUi2lkW3X9sz2gNh2tVJWWMorbCvZADZC1gJZA22vJEjRGmWqXirZC9HKjhtbnZOPD77z2o7Y2bxiNF7P0Y0mHnQwTv89mdygf4S95k0tmYBscPFoEMPPFdOiR5csem8mDGvSoABUU9dM_geaI2dNxUVG3_-D7sIap5zEkWK8ZjVvMiUfqJxdShH7095A9bF5_bR5fd-8PjaflW-ffvuk-1N19RvR8rH-</recordid><startdate>20160701</startdate><enddate>20160701</enddate><creator>Lim, Diane C</creator><creator>Brady, Daniel C</creator><creator>Soans, Rajath</creator><creator>Kim, Emily Y</creator><creator>Valverde, Laise</creator><creator>Keenan, Brendan T</creator><creator>Guo, Xiaofeng</creator><creator>Kim, Woo Young</creator><creator>Park, Min Jeong</creator><creator>Galante, Raymond</creator><creator>Shackleford, James A</creator><creator>Pack, Allan I</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TS</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5748-629X</orcidid></search><sort><creationdate>20160701</creationdate><title>Different cyclical intermittent hypoxia severities have different effects on hippocampal microvasculature</title><author>Lim, Diane C ; Brady, Daniel C ; Soans, Rajath ; Kim, Emily Y ; Valverde, Laise ; Keenan, Brendan T ; Guo, Xiaofeng ; Kim, Woo Young ; Park, Min Jeong ; Galante, Raymond ; Shackleford, James A ; Pack, Allan I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-a7bdbf2cf1eebd688c5c043eb3791e95765e291bf87175ba8a3f787f55b7d4ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Angiogenesis</topic><topic>Angiopoietin-2 - metabolism</topic><topic>Animals</topic><topic>Capillaries - metabolism</topic><topic>Capillaries - physiopathology</topic><topic>Cognitive ability</topic><topic>Disease Models, Animal</topic><topic>Glucose Transporter Type 1 - metabolism</topic><topic>Hippocampus - metabolism</topic><topic>Hippocampus - physiopathology</topic><topic>Hypoxia</topic><topic>Hypoxia - metabolism</topic><topic>Hypoxia - physiopathology</topic><topic>Male</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microvessels - metabolism</topic><topic>Microvessels - physiopathology</topic><topic>Physiology</topic><topic>Receptor, TIE-2 - metabolism</topic><topic>RNA, Messenger - metabolism</topic><topic>Sleep apnea</topic><topic>Sleep Apnea, Obstructive - metabolism</topic><topic>Sleep Apnea, Obstructive - physiopathology</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lim, Diane C</creatorcontrib><creatorcontrib>Brady, Daniel C</creatorcontrib><creatorcontrib>Soans, Rajath</creatorcontrib><creatorcontrib>Kim, Emily Y</creatorcontrib><creatorcontrib>Valverde, Laise</creatorcontrib><creatorcontrib>Keenan, Brendan T</creatorcontrib><creatorcontrib>Guo, Xiaofeng</creatorcontrib><creatorcontrib>Kim, Woo Young</creatorcontrib><creatorcontrib>Park, Min Jeong</creatorcontrib><creatorcontrib>Galante, Raymond</creatorcontrib><creatorcontrib>Shackleford, James A</creatorcontrib><creatorcontrib>Pack, Allan I</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of applied physiology (1985)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lim, Diane C</au><au>Brady, Daniel C</au><au>Soans, Rajath</au><au>Kim, Emily Y</au><au>Valverde, Laise</au><au>Keenan, Brendan T</au><au>Guo, Xiaofeng</au><au>Kim, Woo Young</au><au>Park, Min Jeong</au><au>Galante, Raymond</au><au>Shackleford, James A</au><au>Pack, Allan I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Different cyclical intermittent hypoxia severities have different effects on hippocampal microvasculature</atitle><jtitle>Journal of applied physiology (1985)</jtitle><addtitle>J Appl Physiol (1985)</addtitle><date>2016-07-01</date><risdate>2016</risdate><volume>121</volume><issue>1</issue><spage>78</spage><epage>88</epage><pages>78-88</pages><issn>8750-7587</issn><eissn>1522-1601</eissn><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.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>27125850</pmid><doi>10.1152/japplphysiol.01040.2015</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-5748-629X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Angiogenesis Angiopoietin-2 - metabolism Animals Capillaries - metabolism Capillaries - physiopathology Cognitive ability Disease Models, Animal Glucose Transporter Type 1 - metabolism Hippocampus - metabolism Hippocampus - physiopathology Hypoxia Hypoxia - metabolism Hypoxia - physiopathology Male Metabolism Mice Mice, Inbred C57BL Microvessels - metabolism Microvessels - physiopathology Physiology Receptor, TIE-2 - metabolism RNA, Messenger - metabolism Sleep apnea Sleep Apnea, Obstructive - metabolism Sleep Apnea, Obstructive - physiopathology Vascular Endothelial Growth Factor A - metabolism Vascular Endothelial Growth Factor Receptor-2 - metabolism |
title | Different cyclical intermittent hypoxia severities have different effects on hippocampal microvasculature |
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