Fatty vessels shed tonnes on programmed cardiovascular risk

Cardiovascular disease remains one of the greatest killers in the world today, causing more than a quarter of all deaths in the UK (https://www.bhf.org.uk/for-professionals/press-centre/facts-and-figures). It is common knowledge that cardiovascular risk is determined by the interaction between our genetic make-up and lifestyle risk factors, such as smoking, obesity and lack of exercise. There is increasing awareness that the gene–environment interaction before birth may be just as, if not more, important in setting a risk of cardiovascular disease, through a process known as developmental programming (Giussani & Davidge, 2013). In humans, the best evidence to support developmental programming comes from studies of obese women who have fallen pregnant before and after having bariatric surgery (Guénard et al. 2013). These studies show that siblings born before the surgery have an increased risk of cardiovascular disease compared to those born after. Therefore, such studies highlight that changes in the environment even within the same womb can programme a differential risk of cardiovascular disease in offspring of the same family. This provides strong evidence in humans that the quality of the environment experienced during critical, early periods of development directly influences long-term cardiovascular health. Unsurprisingly, these concepts have renewed and amplified a focus on prevention rather than treatment to reduce the burden of cardiovascular disease, and for preventative medicine to start as early as possible in the developmental trajectory rather than waiting to treat disease after it has become irreversible. 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. In addition to mechanical protection and thermoregulation, the PVAT promotes dilator and anti-contractile effects, mediated through endocrine and paracrine action of biologically active PVAT-relaxation factors. 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. Interestingly, adiponectin levels are inversely proportional to body mass index (BMI), visceral fat accumulation and the levels of glucose, insulin and triglycerides (De Rosa et al. 2013). Further, there is an inverse relationship between adipocyte size and adiponectin secretion (Drolet et al. 2009). Evidence derived from human clinical studies and animal models shows that endothelial dysfunction in the adult offspring is a common adverse outcome of many types of sub-optimal pregnancy (Giussani & Davidge, 2013). Endothelial dysfunction usually presents itself with enhanced constrictor and impaired dilator reactivity, which increases total peripheral vascular resistance, cardiac afterload and thereby the risk of hypertension (Brain et al. 2019). 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. 1). This line of thinking could offer a potential explanation linking the common co-morbidities of endothelial dysfunction, hypertension, increased adiposity and insulin resistance in the adult offspring of many types of adverse pregnancy. None declared. Sole author. D.A.G. is supported by the British Heart Foundation.