Submitted on May 3, 2006
Accepted on July 25, 2006
Increased maternal cortisol in late gestation ewes decreases fetal cardiac expression of 11
-HSD2 mRNA and the ratio of AT1 to AT2 receptor mRNA
Seth A Reini1, Charles E Wood1, Ellen Jensen2, and Maureen Keller-Wood3*
1 Physiology and Functional Genomics, University of Florida, 32610, Florida, United States
2 Physiology, The University of Auckland, Gainesville, Florida, United States
3 Pharmacodynamics, University of Florida, 32610, Florida, United States
* To whom correspondence should be addressed. E-mail: kellerwd{at}cop.ufl.edu.
Moderately elevated maternal cortisol levels late in gestation cause enlargement of the fetal sheep heart. We have used qrt-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/day) or decreased (by adrenalectomy and replacement to 0.5 mg cortisol/kg/day) from 115-130 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), insulin-like growth factors (IGFs) I and II, IGF receptors 1 and 2 (IGF-1R and IGF-2R), endothelial nitric oxide synthase (NOS-3), vascular endothelial growth factor (VEGF), myotrophin, angiotensinogen, the angiotensin receptors (AT1R and AT2R), and the angiotensin converting enzymes (ACE1 and ACE2) 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 angiotensin receptor expression, with increased AT2 and decreased AT1 receptors in the high cortisol group. MR, GR, and 11-HSD1 immunoreactivity was found in cardiomyocytes and cardiac blood vessels in 126-128d 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 (RAS) may play a role.
