A tough life in utero doesn't necessarily make for a stiff future: sex matters for aortic passive mechanics

Life in utero is not all smooth sailing for some. Even in individuals endowed with a ‘perfect’ set of genes, other factors can conspire to make life less than ideal, inducing physiological adaptations in the fetus, some of which persist from the womb right through to the tomb. The cardiovascular system is susceptible to influence by any number of adverse early life environments ranging from maternal nutritional deficiency, hypoxia, kinking of the umbilical cord, maladaptation of the placenta, maternal substance abuse through to lactation and nurturing conditions, to name but a few. Many, but not all, of these adverse early life environments are linked with increased cardiovascular disease risk in the offspring. The seminal work of Barker and colleagues (1989) has spurred intense research interest in the developmental origins of health and disease (DoHAD), with a spotlight on the cardiovascular system and hypertension development. Although the function of the heart and blood vessels has been closely scrutinised, the role of the ‘material’ of the blood vessel wall, or the passive mechanical wall properties, has been less well studied in the context of the DoHAD field. Increased stiffness of the artery wall is a risk factor for cardiovascular disease. For large arteries such as the aorta, recoil of the wall during diastole serves to maintain organ perfusion when the heart is in diastole, a function that is compromised when the aortic wall stiffens. Apart from smooth muscle cells as a ‘substance’ of the vascular wall, the extracellular matrix is an important determinant of the passive mechanical wall properties of the blood vessel wall. Collagen and elastin are important players and impart resilience and flexibility to the blood vessel wall. The quantity, nature, arrangement and crosslinking of the fibres and their interactions influence the stiffness of the arterial wall, which can markedly impact vascular stiffness and cardiovascular disease risk (Townsend et al. 2015). Deposition of elastin in the arterial wall essentially ceases in early postnatal life. Thus, factors that impact on elastogenesis will affect blood vessel flexibility for virtually a lifetime. Although collagen deposition increases markedly during the fetal and neonatal period, it continues to be sculpted throughout life by haemodynamic and hormonal influences. In the maternal undernutrition model (MUN) of fetal growth restriction, only male offspring develop hypertension. The study by Gutiérrez-Arzapalo et al. (2018) in this issue of The Journal of Physiology explored if the sex-dependent manifestation of hypertension is underpinned by differences in the passive mechanical wall properties of the aorta. In an elegant study that pushed the boundaries in the DoHAD field in terms of methods used to explore the nature of the extracellular matrix, the authors revealed structural immaturity of the aortic wall that manifested as reduced stiffness in young offspring of both sexes. This is underpinned by reduced collagen deposition, enhanced compliance of elastin and larger holes in the internal elastic lamina of arteries of MUN offspring. Unlike some other models used in the DoHAD field, increased wall stiffness is not involved in the aetiology of sex-dependent hypertension in this MUN model. Interestingly, however, in adulthood the increased compliance of elastin was maintained in aortae of female offspring only. Whether the loss of elastin compliance in adult males contributes to the manifestation of hypertension awaits further study. Sex hormones can influence the expression and activity of enzymes that are involved in remodelling elements of the extracellular matrix. However, during in utero life, sex-specific modulation of placental function is thought to contribute to sexually dimorphic differences in fetal growth and vitality (Clifton, 2010). This sexually dimorphic influence of the placenta on growth and development is also likely to be important in shaping the phenotype of the passive mechanical wall properties of blood vessels. There is still much to be explored about the effects of early life insults on the passive mechanical wall properties of arteries and their underlying mechanisms. What this article helps to highlight in the context of the DoHAD field is that even if an adverse early life environment culminates in the same outcome, i.e. fetal growth restriction, the nature of the initial insult will differentially influence function in various organs. For example, while aortic wall stiffness was reduced in offspring in this MUN model, in other models of uteroplacental insufficiency large artery stiffness was increased in both growth restricted male and female offspring, or either increased or unchanged in muscular arteries in a vessel-dependent manner in growth restricted male rat offspring (Tare et al. 2012). Thus, the determinants of passive arterial wall stiffness are capable of responding, for better or for worse, to disturbances in early life environment. The phenotype of vascular wall stiffness ultimately reflects the adaptations made in early life and how these have responded to haemodynamic and hormonal influences, the influence of sex hormones and location in the circulation. Over a lifetime, passive arterial wall stiffness will be sculpted by lifestyle influences, disease and, in time, the effects of ageing. The foundations for healthy wall stiffness are laid down very early in life and disruption of this process at this critical time will likely have implications for the passive mechanical wall properties of the vasculature that last a lifetime.