Mechanisms of glucocorticoid programmed disease

Abstract

Substantial epidemiological evidence correlates low weight or thinness at birth with increased risk of disease in later life; notably insulin resistance, hypertension and ischaemic heart disease. This concept of intrauterine life events having permanent influences upon later health has been termed 'programming'. Whilst the molecular mechanisms linking these effects are unknown, overexposure of the foetus to glucocorticoids has been implicated. Treating pregnant rats with dexamethasone (DEX), a synthetic glucocorticoid commonly used in obstetric practice, results in offspring born of low weight, who subsequently develop adulthood hypertension, glucose intolerance and insulin resistance. Whilst prenatal DEX-programmed glucose intolerance is associated with permanently increased hepatic activity of a key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK), mechanisms underlying the programming of hypertension remain unidentified. DEX-programmed hypertension occurs in both sexes, whilst hyperglycaemia/hyperinsulinaemia has only been demonstrated in male offspring. Principally, this thesis investigates the role of the renin-angiotensin (RAS), and sympathetic nervous systems (SNS) in determining programmed hypertension, and seeks to determine whether programming effects are sexually dimoiphic. ft further examines the impact of dietary manipulations, and environmental noise stress, on prenatally-treated offspring phenotypes.DEX administration in the last week of gestation reduces offspring birth weight and programmes adult cardiovascular and metabolic physiology in a sex specific manner. In male offspring, prenatal glucocorticoid exposure programmes elevated basal circulating corticosterone, elevated PEPCK activity, and produces adulthood post-glucose hyperglycaemia and hyperinsulinaemia. Whilst in female offspring, prenatal DEX programmes elevated hepatic angiotensinogen mRNA expression, elevated plasma angiotensinogen and renin activity, and produces hypertension, when measured by tail-cuff plethysmography.A 4-fold reduction in dietary sodium intensifies this RAS dysregulation in female DEX-treated offspring; however this does not exacerbate their programmed blood pressure phenotype. Conversely, the lower sodium diet results in hypertension in prenatally vehicle treated animals, and supports a role for both the HPA and RAS in mediating this. Furthermore, acute exposure to the lower sodium diet is sufficient to cause glucose intolerance and insulin resistance in female adult rats, irrespective of their prenatal treatment.Unlike previous studies, offspring blood pressure was subsequently assessed with radiotelemetry, which is unmarred by any stress artefact. We now show that prenatal DEX-treated male and female offspring actually display lower basal blood pressure in adulthood; with the commonly expected hypertensive phenotype only being noted when these offspring are subjected to any stressor, regardless of its apparent banality. Moreover, DEX-treated offspring sustain this stress-induced hypertension for longer. These hypertensive responses are mediated by alterations in the responsivity of the sympathetic nervous system, being ameliorated by the inhibition of catecholamine synthesis, and further exaggerated by the promotion of systemic catecholamine release. Additionally, we demonstrate that DEX-treated offspring display greater sensitivity to various vasoconstrictors in the isolated mesenteric vasculature.Finally, perinatal exposure of pregnant rats to environmental noise pollution results in vehicle-treated offspring with a phenotype analogous to prenatal DEXtreated offspring i.e. lower birth weight, hypercorticosteronaemia, hypertension, and features of the insulin resistance syndrome. Conversely, exposure of DEX-treated offspring to the same perinatal noise stressors does not appear to further influence their phenotype. Therefore, perinatal stress produces a similar phenotype to prenatal glucocorticoid over-exposure.These findings demonstrate that in utero over-exposure to glucocorticoids actually results in stress-induced hypertension, and support a role for both RAS and SNS in mediating this. Furthermore, it appears that the programming of cardiovascular physiology may reflect distinct processes in each gender, whilst the programming of metabolic physiology is male specific.