Prenatal Exposure to Dexamethasone in the Mouse Alters Cardiac Growth Patterns and Increases Pulse Pressure in Aged Male Offspring

Abstract

Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ∼3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance.

Glucocorticoids and foetal heart maturation; implications for prematurity and foetal programming

“…However, when cortisol was infused into the coronary artery of foetal sheep, hyperplasia was induced with only a modest increase in intracardiac cortisol (threefold) and without blood pressure changes (Torres et al 1997, Giraud et al 2006, suggesting a pro-proliferative effect of cortisol on cardiomyocytes. A recent study on mice has administered dexamethasone from E12.5 to E15 (before the normal glucocorticoid surge; O'Sullivan et al 2013). Although this caused a transient decrease in foetal weight and a corresponding though non-significant decrease in foetal heart weight at E14.5, this had recovered by E17.5, possibly as a result of increased cardiac expression of insulin-like growth factor 1, and cardiomyocyte number in adulthood was unchanged (O'Sullivan et al 2013), suggesting compensatory myocardial growth once dexamethasone treatment stopped (though glucocorticoidregulated mRNAs remained elevated at E17.5, indicating a lasting effect of glucocorticoid action on foetal cardiomyocytes).…”

“…A recent study on mice has administered dexamethasone from E12.5 to E15 (before the normal glucocorticoid surge; O'Sullivan et al 2013). Although this caused a transient decrease in foetal weight and a corresponding though non-significant decrease in foetal heart weight at E14.5, this had recovered by E17.5, possibly as a result of increased cardiac expression of insulin-like growth factor 1, and cardiomyocyte number in adulthood was unchanged (O'Sullivan et al 2013), suggesting compensatory myocardial growth once dexamethasone treatment stopped (though glucocorticoidregulated mRNAs remained elevated at E17.5, indicating a lasting effect of glucocorticoid action on foetal cardiomyocytes). However, the possibility of foetal HPA axis suppression by dexamethasone treatment was not examined in that study, so it is unclear whether the normal increase in glucocorticoid levels at E16.5-E18.5 occurred in the treated mice and it is likely that the late gestation trajectory of heart maturation was altered in response to dexamethasone.…”

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

“…However, maternal glucocorticoids may not directly cause the hypertension in the offspring [94]. It has been suggested that the inconsistency in the increase in BP after prenatal exposure to glucocorticoids in rodents could indicate that hypertension becomes apparent only under stressed conditions and that the use of tail cuff to measure BP contributed to the irregularity [95]. The absence of glucocorticoid-inducible kinase SGK1 in the mother prevents the ability of prenatal protein restriction to increase the BP in adult male and female offspring.…”

Has the Fluocinolon-acetonid N ointment any effect on the kidneys and the thyroid gland structure and function?

“…In addition to the direct effects of glucocorticoids, they can indirectly modify the vascular response, too. Glucocorticoids inhibit prostanoid synthesis, and this mechanism also prevents prostanoid induced vasodilatation (O'Sullivan et al, 2013). The decreased level of glucocorticoids, in Addison-disease or after the removal of the adrenals, caused chronic low blood pressure in many patients (Fonyó, 2011).…”