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 ( $F_{I{O}_2}$ 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 associated with low adiponectin levels and epigenetic modifications on the adiponectin gene promoter.