Suboptimal intrauterine environments are known to affect the growth and development of the fetoplacental unit. These changes have been associated with an increased risk of developing disease in later life. Glucocorticoids are frequently administered to women at risk of delivering a preterm infant, as well as being a routine therapy for the treatment of anti-inflammatory conditions such as asthma. Glucocorticoids are also naturally occurring hormones in the maternal circulation and their production and release is elevated during times of stress. Exposure to elevated levels of glucocorticoids during fetal development is linked to impaired fetal growth, structural and functional changes to the kidney, heart and vasculature in exposed offspring. These changes can persist throughout life increasing the susceptibility to diseases such as hypertension and metabolic syndrome disorders. We have established a model of short-term, mid-gestational glucocorticoid exposure in the mouse. This thesis aims to look at the roles played by synthetic and endogenous glucocorticoids in the programming of adult cardiovascular and renal disease.
First, we investigated the impact of the synthetic glucocorticoid dexamethasone (DEX) on fetal heart growth, and adult blood pressure. DEX exposure caused a transient reduction in heart weight at embryonic day (E)14.5. By E17.5, the heart weight of DEX exposed fetuses were not different to that of saline (SAL) controls. This ‘catch up’ in heart growth was associated with elevated cardiac mRNA levels at E17.5 of the cardiotrophic genes IGF-1 and AT1aR. Cardiomyocyte number was not affected by DEX treatment. DEX exposed offspring had a slight increase in mean arterial pressure (~3 mmHg) at 12 months of age compared to SAL controls, as well as increased pulse pressure. Additionally, DEX exposed offspring have an ~ 25% reduction in nephron number. In response to a restraint stress challenge, DEX exposed offspring did not have an exaggerated pressor response compared to SAL control. There were tendencies for DEX exposed offspring to have an attenuated heart rate response and a further widening of their pulse pressure during restraint compared to controls. The difference in pulse pressure may be due to alterations in vascular compliance.
Second, we have shown that exposure to increased levels of maternal corticosterone (CORT) acts in a sex-specific manner in programming cardiovascular and renal dysfunction in exposed offspring. CORT exposed fetuses at E17.5 weighed less than untreated (UNTR) controls. Heart weight was lower at both E14.5 and E17.5 in CORT exposed fetuses. In contrast to the DEX study, there was a i absence of ‘catch up’ growth in CORT exposed fetal hearts. This may in part be due to a lack of increase in the gene expression of cardiac growth factors. The CORT exposed male offspring mesenteric arteries were inwardly remodeled around a narrower lumen, and were more distensible under hydrostatic loading conditions than UNTR vessels at 7 months of age. No differences in vascular function were seen in between treatment groups in either sex. At 12 months of age the males exposed to prenatal CORT exhibited a marked hypotension compared to UNTR males, but no differences in blood pressures were seen females. In response to a restraint stress CORT males were unable to sustain their tachycardic response, but no difference in pressor response to restraint were observed in either sex. There was a shift in the sympathovagal control of heart rate variability in both basal and stressed conditions, which favoured vagal dominance of heart rate variation. Whether the hypotensive phenotype in the males is pathophysiological, adaptive, or even protective remains unknown.
Third, we have investigated the impact of long-term high-salt (HS) feeding in CORT exposed offspring. Long-term HS feeding led to an exacerbation of the inward remodelling seen in CORT exposed males. CORT exposed HS fed females had the most severe inward remodelling of any of the groups as well as an increased media to lumen ratio, despite prenatal CORT alone having no significant effect on vascular structure in female offspring. HS feeding did not lead to any difference in vascular function in either sex.
In conclusion, the glucocorticoid induced programming of cardiovascular and renal phenotypes in the mouse is a glucocorticoid specific, and sex-specific phenomenon. The effects of excess prenatal CORT exposure had longer lasting effects on the developing fetus when compared to those of prenatal DEX. These effects led to pronounced differences in long-term renal and cardiovascular function in later life. These findings provide further insights into the mechanisms of glucocorticoid induced fetal programming of renal and cardiovascular disease. They highlight the susceptibility of male offspring born to women who may have been subjected to psychosocial or physical trauma. The identification and close monitoring of children exposed to prenatal maternal stress may present opportunities for early intervention, and therefore reduce the burden of disease.