Intermittent hypoxia impairs uterine artery function in pregnant mice

Abstract

Key pointsr Obstructive sleep apnoea (OSA) is a chronic condition characterized by intermittent hypoxia that induces oxidative stress and inflammation leading to cardiovascular disease.r Women can develop OSA during late pregnancy, which is associated with adverse maternal and fetal outcomes. However, the effects of OSA throughout pregnancy on fetoplacental outcomes are unknown.r Using a mouse model of intermittent hypoxia, we evaluated main uterine artery function, spiral artery remodelling, circulating angiogenic and anti-angiogenic factors, and placental hypoxia and oxidative stress at gestational day 14.5 in pregnant mice. r Gestational intermittent hypoxia increased placental weight but decreased fetal weight, impaired uterine artery function, increased circulating angiogenic and anti-angiogenic factors, and induced placental hypoxia and oxidative stress, but had no impact on spiral artery remodelling.r Our results suggest that pregnant women experiencing OSA during pregnancy could be at risk of maternal and fetal complications.Abstract Obstructive sleep apnoea (OSA) is characterized by chronic intermittent hypoxia (IH) and is associated with increased inflammation, oxidative stress and endothelial dysfunction. OSA is a common sleep disorder and remains under-diagnosed; it can increase the risk of adverse maternal and fetal outcomes in pregnant women. We investigated the effects of gestational IH (GIH) on uterine artery function, spiral artery remodelling and placental circulating angiogenic and anti-angiogenic factors in pregnant female mice. WT C57BL/6 mice (8 weeks) were exposed to either GIH (F IO 2 12%) or intermittent air (F IO 2 21%) for 14.5 days of gestation. Exposure to GIH reduced fetal weight but increased placental weight. GIH dams Mohammad Badran is a PhD candidate in the Department of Anesthesiology, Pharmacology & Therapeutics at the University of British Columbia, investigating vascular outcomes and developmental programming in a mouse model of sleep apnoea. His research opens a new frontier in identifying therapeutic candidates for the management of obstructive sleep apnoea (OSA) and provides insight into the pathophysiology of OSA in pregnancy. This work may be important in understanding the cardiometabolic disease in adult offspring exposed to gestational hypoxia resulting from maternal OSA. M. Badran and othersJ Physiol 597.10 had higher plasma levels of oxidative stress (8-isoprostane) and inflammatory markers (tumour necrosis factor-α). GIH significantly reduced uterine artery function as indicated by reduced endothelium-dependent vasodilatation and enhanced vasoconstriction. Plasma levels of placental angiogenic and anti-angiogenic markers (soluble fms-like tyrosine kinase-1, soluble endoglin, angiogenic placental growth factor-2 and vascular endothelial growth factor) were higher in pregnant mice exposed to GIH. There was no evidence of impaired spiral artery remodelling based on immunostaining with α-smooth muscle actin and cytokeratin-7, and also by measurements of lumen area. Immu...

Placental oxygen transfer reduces hypoxia-reoxygenation swings in fetal blood in a sheep model of gestational sleep apnea

“…The present study was carried out in a sheep model rather than the most commonly used rodent models that have previously explored the effects of maternal OSA on the fetus and offspring (3,13,35,36,38). A minor, but certainly not negligible, advantage of the ovine model is that the size of both mother and fetus (usually single gestation) are very close to those in humans, thereby facilitating local measurements and tissue biopsy at different fetal organs and, most importantly, allowing for implantation of telemetric sensors to monitor physiological signals in the developing fetus subjected to maternal OSA from mid to late gestation.…”

“…25,28,33,39,61), OSA poses a specific challenge during pregnancy. Indeed, both clinical and animal studies have shown that OSA imposes significant risk accrual for the emergence of diabetes and preeclampsia in pregnant women, and increased risk for metabolic syndrome is apparent in offspring both short term and long term and is even transmitted across generations (3,13,35,36,38,52,69).…”

miR-3574 ameliorates intermittent hypoxia-induced cardiomyocyte injury through inhibiting Axin1

“…There is increased recognition that OSA, characterized by intermittent hypoxia (IH), is deemed as a risk factor for the development of many cardiovascular diseases such as hypertension [ 4 ], myocardial ischemia [ 6 ], heart failure [ 7 ], atherosclerosis [ 17 ], and coronary artery disease [ 18 ]. The IH leads to a number of potential adverse consequences, including activation of inflammation [ 19 ], insulin resistance [ 20 ], oxidative stress [ 21 ], sympathetic activation [ 22 ], and endothelial dysfunction [ 23 ]. Thus, it contributes to OSA-associated cardiovascular pathologies.…”

Placental oxygen transfer reduces hypoxia/reoxygenation swings in fetal blood in a sheep model of gestational sleep apnea

“…The present study was carried out in a sheep model rather than the most commonly used rodent models which have previously explored the effects of maternal OSA on the fetus and offspring (3,13,35,37,40). A minor, but certainly not negligible advantage of the ovine model is that the size of both mother and fetus (usually single-gestation) are very close to those in humans, thereby facilitating local measurements and tissue biopsy at different fetal organs and most importantly, allowing for implantation of telemetric sensors to monitor physiological signals in the developing fetus subjected to maternal OSA from mid to late gestation.…”

“…increase in morbidity and mortality by cardiocirculatory, metabolic, neurocognitive and malignant diseases (25,28,33,38,61), OSA poses a specific challenge during pregnancy. Indeed, both clinical and animal studies have shown that OSA imposes significant risk accrual for the emergence diabetes and pre-eclampsia in pregnant women, while increased risk for metabolic syndrome is apparent in offspring both shortterm and long-term, and even transmitted across generations (3,13,35,37,40,52,69).…”