Intermittent hypoxia impairs uterine artery function in pregnant mice.

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 I O 2 12%) or intermittent air ( F I O 2 21%) for 14.5 days of gestation. Exposure to GIH reduced fetal weight but increased placental weight. GIH dams 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. Immunostaining for markers of hypoxia (pimonidazole) and oxidative stress (4-hydroxynonenal) were higher in mice exposed to GIH. Our data show that GIH adversely affects uterine vascular function and may be a mechanism by which gestational OSA leads to adverse maternal and fetal outcomes.