Gestational intermittent hypoxia induces endothelial dysfunction, reduces perivascular adiponectin and causes epigenetic changes in adult male offspring

Abstract

Key points Obstructive sleep apnoea (OSA) is characterized by intermittent hypoxia, which causes oxidative stress and inflammation and increases the risk of cardiovascular disease. OSA during pregnancy causes adverse maternal and fetal outcomes. The effects of pre‐existing OSA in pregnant women on cardiometabolic outcomes in the offspring are unknown. We evaluated basic metabolic parameters, as well as aortic vascular and perivascular adipose tissue (PVAT) function in response to adiponectin, and examined DNA methylation of adiponectin gene promoter in PVAT in 16‐week‐old adult offspring exposed to gestational intermittent hypoxia (GIH). GIH decreased body weights at week 1 in both male and female offspring, and caused subsequent increases in body weight and food consumption in male offspring only. Adult female offspring had normal levels of lipids, glucose and insulin, with no endothelial dysfunction. Adult male offspring exhibited dyslipidaemia, insulin resistance and hyperleptinaemia. Decreased endothelial‐dependent vasodilatation, loss of anti‐contractile activity of PVAT and low circulating PVAT adiponectin levels, as well as increased pro‐inflammatory gene expression and DNA methylation of adiponectin gene promoter, occurred in adult male offspring. Our results suggest that male offspring of women with OSA could be at risk of developing cardiometabolic disease during adulthood. Abstract Perturbations during pregnancy can program the offspring to develop cardiometabolic diseases later in life. Obstructive sleep apnoea (OSA) is a chronic condition that frequently affects pregnancies and leads to adverse fetal outcomes. We assessed the offspring of female mice experiencing gestational intermittent hypoxia (GIH), a hallmark of OSA, for changes in metabolic profiles, aortic nitric oxide (NO)‐dependent relaxations, perivascular adipose tissue (PVAT) anti‐contractile activities and the responses to adiponectin, and DNA methylation of the adiponectin gene promoter in PVAT tissue. Pregnant mouse dams were exposed to intermittent hypoxic cycles (FnormalIO2 21–12%) for 18 days. GIH resulted in lower body weights of pups at week 1, followed by significant weight gain by week 16 of age in male but not female offspring. Plasma lipids, leptin and insulin resistance were higher in GIH male adult offspring. Endothelium‐dependent relaxation in response to ACh and the anti‐contractile activity of PVAT in the abdominal aorta was reduced in GIH adult male offspring. Incubation of arteries from GIH adult male offspring with adiponectin restored the anti‐contractile activity of PVAT. Both circulating and PVAT tissue homogenate levels of adiponectin, as well as gene expression of adiponectin in PVAT, were lower in GIH male offspring, along with an increased gene expression of inflammatory cytokines. Pyrosequencing of adiponectin gene promoter in PVAT showed increased DNA methylation in GIH male offspring. Our results indicate that GIH leads to vascular disease in adult male offspring through PVAT dysfunction, which was associate...

Fatty vessels shed tonnes on programmed cardiovascular risk

“…Obstructive sleep apnoea is characterized by episodes of intermittent hypoxia, which promote oxidative and inflammatory stress, and increase the risk of cardiovascular dysfunction in affected patients (Badran et al . ). However, animal models have not addressed the effects of maternal obstructive sleep apnoea during pregnancy on the cardiovascular health of the offspring.…”

“…In this issue of The Journal of Physiology, Badran et al (2019) investigated the effects of obstructive sleep apnoea during pregnancy on cardiometabolic function in the adult offspring using an established mouse model. Obstructive sleep apnoea is characterized by episodes of intermittent hypoxia, which promote oxidative and inflammatory stress, and increase the risk of cardiovascular dysfunction in affected patients (Badran et al 2019). However, animal models have not addressed the effects of maternal obstructive sleep apnoea during pregnancy on the cardiovascular health of the offspring.…”

“…Further, there are currently no clinical studies on obstructive sleep apnoea and developmental programming of cardiometabolic disease. This gap of knowledge is important given that obstructive sleep apnoea is associated with obesity and the rates of maternal obesity during pregnancy are increasing (Badran et al 2019). The study evaluated alterations in metabolic outcomes, vascular reactivity and the function of perivascular adipose tissue (PVAT) in the adult offspring.…”

“…The identities of such factors are still becoming elucidated but they may include agents, such as hydrogen peroxide, hydrogen sulphide, nitric oxide and adiponectin (Brown et al 2014). Badran et al (2019) reported that intermittent hypoxia in their mouse model of obstructive sleep apnoea during pregnancy programmed insulin resistance, increased adiposity and impaired endothelium-dependent relaxation in male but not female adult offspring. In addition, male offspring of pregnancy complicated by intermittent hypoxia showed hypermethylation of the adiponectin gene promoter, lower levels of adiponectin and loss of anti-contractile activity in the PVAT, an effect that could be improved by adding adiponectin ex vivo.…”

“…It is also known that endothelial dysfunction and hypertension are coupled with increased adiposity and insulin resistance in adult offspring of many types of sub-optimal pregnancy complicated by adverse intrauterine conditions (Giussani & Davidge, 2013). Therefore, the study of Badran et al (2019) not only reports programmed adverse cardiometabolic effects in the adult offspring in a novel model of developmental programming of pregnancy complicated by maternal obstructive apnoea, but also introduces the field to the important modulatory effects of the PVAT on vascular function. A testable hypothesis offering a rich avenue of future research would therefore state that adverse conditions during pregnancy programme an increased risk of adiposity in the adult offspring, impairing the dilator and anti-contractile effects of PVAT, thereby increasing the risk of endothelial dysfunction and cardiovascular disease (Fig.…”