Skip to main content
Top
Published in: Sleep and Breathing 4/2022

29-11-2021 | Sleep Apnea | Sleep Breathing Physiology and Disorders • Original Article

Gestational chronic intermittent hypoxia induces hypertension, proteinuria, and fetal growth restriction in mice

Authors: Cuilian Weng, Long Huang, Hangwei Feng, Quanying He, Xingsheng Lin, Tingting Jiang, Jian Lin, Xincai Wang, Qinghua Liu

Published in: Sleep and Breathing | Issue 4/2022

Login to get access

Abstract

Purpose

Pregnant women are predisposed to obstructive sleep apnea (OSA). Based on the fact that OSA is an independent risk factor for hypertension among the general population, we hypothesized that chronic intermittent hypoxia (CIH), as a feature of OSA, may lead to preeclampsia.

Methods

Pregnant and non-pregnant C57BL/6 J mice were exposed to two conditions of chronic intermittent hypoxia: CIH1 (21–5% O2 alternations), CIH2 (21–10% O2 alternations), and room air until day 19.

Results

In non-pregnant mice, compared with their respective baseline values, systolic blood pressure (SBP) started to rise from day 14 in the CIH1 group, and SBP rose until day 19 in the CIH2 group. Compared with the pregnant mice exposed to room air, pregnant mice exposed to CIH1 maintained elevated SBP from day 14, accompanied by proteinuria, fetal and placental growth restriction, and a reduction in the number of fetuses. An imbalance between proangiogenic and antiangiogenic factors and impairment of vascular remodeling existed in the placenta of pregnant mice exposed to CIH1. Maternal serum levels of the soluble form of vascular endothelial growth factor receptor-1 were also significantly increased. Pregnant mice exposed to CIH2 seemed to have milder changes than pregnant mice exposed to CIH1.

Conclusion

Our results demonstrated that gestational CIH may induce gestational hypertension, proteinuria, fetal and placental growth restriction as well as impairments in placental angiogenesis and vascular remodeling.
Appendix
Available only for authorised users
Literature
1.
go back to reference Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S (1993) The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328:1230–1235CrossRefPubMed Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S (1993) The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328:1230–1235CrossRefPubMed
3.
go back to reference Louis JM, Koch MA, Reddy UM, Silver RM, Parker CB, Facco FL, Redline S, Nhan-Chang CL, Chung JH, Pien GW, Basner RC, Grobman WA, Wing DA, Simhan HN, Haas DM, Mercer BM, Parry S, Mobley D, Carper B, Saade GR, Schubert FP, Zee PC (2018) Predictors of sleep-disordered breathing in pregnancy. Am J Obstet Gynecol 218(521):e1-521.e12 Louis JM, Koch MA, Reddy UM, Silver RM, Parker CB, Facco FL, Redline S, Nhan-Chang CL, Chung JH, Pien GW, Basner RC, Grobman WA, Wing DA, Simhan HN, Haas DM, Mercer BM, Parry S, Mobley D, Carper B, Saade GR, Schubert FP, Zee PC (2018) Predictors of sleep-disordered breathing in pregnancy. Am J Obstet Gynecol 218(521):e1-521.e12
4.
go back to reference Spence DL, Allen RC, Lutgendorf MA, Gary VR, Richard JD, Gonzalez SC (2017) Association of obstructive sleep apnea with adverse pregnancy-related outcomes in military hospitals. Eur J Obstet Gynecol Reprod Biol 210:166–172CrossRefPubMed Spence DL, Allen RC, Lutgendorf MA, Gary VR, Richard JD, Gonzalez SC (2017) Association of obstructive sleep apnea with adverse pregnancy-related outcomes in military hospitals. Eur J Obstet Gynecol Reprod Biol 210:166–172CrossRefPubMed
5.
go back to reference Fried G, Samuelson U (1991) Endothelin and neuropeptide Y are vasoconstrictors in human uterine blood vessels. Am J Obstet Gynecol 164:1330–1336CrossRefPubMed Fried G, Samuelson U (1991) Endothelin and neuropeptide Y are vasoconstrictors in human uterine blood vessels. Am J Obstet Gynecol 164:1330–1336CrossRefPubMed
6.
go back to reference Lefcourt LA, Rodis JF (1996) Obstructive sleep apnea in pregnancy. Obstet Gynecol Surv 51:503–506CrossRefPubMed Lefcourt LA, Rodis JF (1996) Obstructive sleep apnea in pregnancy. Obstet Gynecol Surv 51:503–506CrossRefPubMed
7.
go back to reference Facco FL, Parker CB, Reddy UM, Silver RM, Koch MA, Louis JM, Basner RC, Chung JH, Nhan-Chang CL, Pien GW, Redline S, Grobman WA, Wing DA, Simhan HN, Haas DM, Mercer BM, Parry S, Mobley D, Hunter S, Saade GR, Schubert FP, Zee PC (2017) Association between sleep disordered breathing and hypertensive disorders of pregnancy and gestational diabetes mellitus. Obstet Gynecol 129(1):31–41CrossRefPubMedPubMedCentral Facco FL, Parker CB, Reddy UM, Silver RM, Koch MA, Louis JM, Basner RC, Chung JH, Nhan-Chang CL, Pien GW, Redline S, Grobman WA, Wing DA, Simhan HN, Haas DM, Mercer BM, Parry S, Mobley D, Hunter S, Saade GR, Schubert FP, Zee PC (2017) Association between sleep disordered breathing and hypertensive disorders of pregnancy and gestational diabetes mellitus. Obstet Gynecol 129(1):31–41CrossRefPubMedPubMedCentral
8.
go back to reference Charbonneau M, Falcone T, Cosio MG, Levy RD (1991) Obstructive sleep apnea during pregnancy. Therapy and implications for fetal health. Am Rev Respir Dis 144:461–463CrossRefPubMed Charbonneau M, Falcone T, Cosio MG, Levy RD (1991) Obstructive sleep apnea during pregnancy. Therapy and implications for fetal health. Am Rev Respir Dis 144:461–463CrossRefPubMed
9.
go back to reference Sahin FK, Koken G, Cosar E, Saylan F, Fidan F et al (2008) Obstructive sleep apnea in pregnancy and fetal outcome. Int J Gynaecol Obstet 100:141–146CrossRefPubMed Sahin FK, Koken G, Cosar E, Saylan F, Fidan F et al (2008) Obstructive sleep apnea in pregnancy and fetal outcome. Int J Gynaecol Obstet 100:141–146CrossRefPubMed
10.
go back to reference Brain KA, Thornton JG, Sarkar A, Johnson AO (2001) Obstructive sleep apnoea and fetal death: successful treatment with continuous positive airway pressure. BJOG 108:543–544PubMed Brain KA, Thornton JG, Sarkar A, Johnson AO (2001) Obstructive sleep apnoea and fetal death: successful treatment with continuous positive airway pressure. BJOG 108:543–544PubMed
11.
go back to reference Guilleminault C, Querra-Salva M, Chowdhuri S, Poyares D (2000) Normal pregnancy, daytime sleeping, snoring and blood pressure. Sleep Med 1:289–297CrossRefPubMed Guilleminault C, Querra-Salva M, Chowdhuri S, Poyares D (2000) Normal pregnancy, daytime sleeping, snoring and blood pressure. Sleep Med 1:289–297CrossRefPubMed
12.
go back to reference Yin TT, Williams N, Burton C, Ong SS, Loughna P, Britton JR, Thornton JG (2008) Hypertension, fetal growth restriction and obstructive sleep apnoea in pregnancy. Eur J Obstet Gynecol Reprod Biol 141:35–38CrossRefPubMed Yin TT, Williams N, Burton C, Ong SS, Loughna P, Britton JR, Thornton JG (2008) Hypertension, fetal growth restriction and obstructive sleep apnoea in pregnancy. Eur J Obstet Gynecol Reprod Biol 141:35–38CrossRefPubMed
14.
go back to reference Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7:359–371CrossRefPubMed Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7:359–371CrossRefPubMed
15.
go back to reference Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi AS (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658CrossRefPubMedPubMedCentral Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi AS (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658CrossRefPubMedPubMedCentral
16.
go back to reference Redman CW, Sargent IL (2005) Latest advances in understanding preeclampsia. Science 308:1592–1594CrossRefPubMed Redman CW, Sargent IL (2005) Latest advances in understanding preeclampsia. Science 308:1592–1594CrossRefPubMed
17.
go back to reference Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai Baha M, Sukhatme Vikas P, AnanthKarumanchi S (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683CrossRefPubMed Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai Baha M, Sukhatme Vikas P, AnanthKarumanchi S (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683CrossRefPubMed
18.
go back to reference Gilbert JS, Babcock SA, Granger JP (2007) Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression. Hypertension 50:1142–1147CrossRefPubMed Gilbert JS, Babcock SA, Granger JP (2007) Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression. Hypertension 50:1142–1147CrossRefPubMed
19.
go back to reference Allahdadi KJ, Walker BR, Kanagy NL (2005) Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension. Hypertension 45:705–709CrossRefPubMed Allahdadi KJ, Walker BR, Kanagy NL (2005) Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension. Hypertension 45:705–709CrossRefPubMed
20.
go back to reference Castro-Grattoni AL, Suarez-Giron M, Benitez I, Torres M, Almendros I, Farre R, Montserrat JM, Dalmases M, Gozal D, Sánchez-de-la-Torre M, Spanish Sleep Network (2020) Effect of age on the cardiovascular remodelling induced by chronic intermittent hypoxia as a murine model of sleep apnoea. Respirology 25:312–320CrossRefPubMed Castro-Grattoni AL, Suarez-Giron M, Benitez I, Torres M, Almendros I, Farre R, Montserrat JM, Dalmases M, Gozal D, Sánchez-de-la-Torre M, Spanish Sleep Network (2020) Effect of age on the cardiovascular remodelling induced by chronic intermittent hypoxia as a murine model of sleep apnoea. Respirology 25:312–320CrossRefPubMed
21.
go back to reference Badran M, Yassin BA, Lin DTS, Kobor MS, Ayas N, Laher I (2019) Gestational intermittent hypoxia induces endothelial dysfunction, reduces perivascular adiponectin and causes epigenetic changes in adult male offspring. J Physiol 597:5349–5364CrossRefPubMed Badran M, Yassin BA, Lin DTS, Kobor MS, Ayas N, Laher I (2019) Gestational intermittent hypoxia induces endothelial dysfunction, reduces perivascular adiponectin and causes epigenetic changes in adult male offspring. J Physiol 597:5349–5364CrossRefPubMed
22.
23.
go back to reference Shibuya M (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 153(1):13–19CrossRefPubMed Shibuya M (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 153(1):13–19CrossRefPubMed
24.
go back to reference Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mihu C, Istrate M, Moldovan IM, Roman AL, Mihu CM (2018) Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 59(2):455–467PubMed Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mihu C, Istrate M, Moldovan IM, Roman AL, Mihu CM (2018) Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 59(2):455–467PubMed
25.
go back to reference Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60CrossRefPubMed Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60CrossRefPubMed
26.
go back to reference Tsiamis AC, Morris PN, Marron MB, Brindle NP (2002) Vascular endothelial growth factor modulates the Tie-2:Tie-1 receptor complex. Microvasc Res 63:149–158CrossRefPubMed Tsiamis AC, Morris PN, Marron MB, Brindle NP (2002) Vascular endothelial growth factor modulates the Tie-2:Tie-1 receptor complex. Microvasc Res 63:149–158CrossRefPubMed
27.
go back to reference Marron MB, Singh H, Tahir TA, Kavumkal J, Kim HZ, Kim HZ, Koh GY, Brindle NPJ (2007) Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem 282:30509–30517CrossRefPubMed Marron MB, Singh H, Tahir TA, Kavumkal J, Kim HZ, Kim HZ, Koh GY, Brindle NPJ (2007) Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem 282:30509–30517CrossRefPubMed
Metadata
Title
Gestational chronic intermittent hypoxia induces hypertension, proteinuria, and fetal growth restriction in mice
Authors
Cuilian Weng
Long Huang
Hangwei Feng
Quanying He
Xingsheng Lin
Tingting Jiang
Jian Lin
Xincai Wang
Qinghua Liu
Publication date
29-11-2021
Publisher
Springer International Publishing
Published in
Sleep and Breathing / Issue 4/2022
Print ISSN: 1520-9512
Electronic ISSN: 1522-1709
DOI
https://doi.org/10.1007/s11325-021-02529-3

Other articles of this Issue 4/2022

Sleep and Breathing 4/2022 Go to the issue

Sleep Breathing Physiology and Disorders • Original Article

Consumer-grade sleep trackers are still not up to par compared to polysomnography

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.