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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Increased maternal cortisol in late-gestation ewes decreases fetal cardiac expression of 11-HSD2 mRNA and the ratio of AT1 to AT2 receptor mRNA

¹Department of Pharmacodynamics, College of Pharmacy and ²Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida

Submitted 3 May 2006 ; accepted in final form 25 July 2006

Moderately elevated maternal cortisol levels late in gestation cause enlargement of the fetal sheep heart. We have used quantitative real-time PCR to examine expression of candidate genes in fetal hearts from mothers in whom cortisol levels were increased (by infusion of 1 mg cortisol·kg^–1·day^–1) or decreased (by adrenalectomy and replacement to 0.5 mg cortisol·kg^–1·day^–1) from 115 to 130 days gestation. Control ewes were not treated with steroid. Expression of mineralocorticoid receptor (MR), glucocorticoid receptor (GR), 11-hydroxysteroid dehydrogenases 1 and 2 (11-HSD1 and -2), IGF I and II, IGF receptors 1 and 2 (IGF-1R and IGF-2R), endothelial nitric oxide synthase, VEGF, myotrophin, angiotensinogen, the angiotensin receptors 1 and 2 (AT1R and AT2R), and the angiotensin converting enzymes 1 and 2 were measured. MR mRNA abundance in fetal hearts was found to be similar to that in adult kidney and hippocampus. Although there were no significant changes in most genes, 11-HSD2 and IGF-1R expression were significantly decreased in the high cortisol group and 11-HSD2 expression negatively correlated to left ventricular wall thickness. There was also a significant change in the ratio of AT receptor expression, with increased AT2R and decreased AT1R in the high cortisol group. MR, GR, and 11-HSD1 immunoreactivity was found in cardiomyocytes and cardiac blood vessels in 126–128 day fetal sheep; in contrast 11-HSD2 staining was predominantly in blood vessels. These results indicate that cortisol could indeed act in the fetal heart to induce enlargement and suggest that the renin-angiotensin system may play a role.

myotrophin; insulin-like growth factor