Oxidative Stress Mediates the Fetal Programming of Hypertension by Glucocorticoids.

The field of cardiovascular fetal programming has emphasized the importance of the uterine environment on postnatal cardiovascular health. Studies have linked increased fetal glucocorticoid exposure, either from exogenous sources (such as dexamethasone (Dex) injections), or from maternal stress, to the development of adult cardiovascular pathologies. Although the mechanisms are not fully understood, alterations in gene expression driven by altered oxidative stress and epigenetic pathways are implicated in glucocorticoid-mediated cardiovascular programming. Antioxidants, such as the naturally occurring polyphenol epigallocatechin gallate (EGCG), or the superoxide dismutase (SOD) 4-hydroxy-TEMPO (TEMPOL), have shown promise in the prevention of cardiovascular dysfunction and programming. This study investigated maternal antioxidant administration with EGCG or TEMPOL and their ability to attenuate the fetal programming of hypertension via Dex injections in WKY rats. Results from this study indicate that, while Dex-programming increased blood pressure in male and female adult offspring, administration of EGCG or TEMPOL via maternal drinking water attenuated Dex-programmed increases in blood pressure, as well as changes in adrenal mRNA and protein levels of catecholamine biosynthetic enzymes phenylalanine hydroxylase (), tyrosine hydroxylase (), dopamine beta hydroxylase (), and phenylethanolamine N-methyltransferase (), in a sex-specific manner. Furthermore, programmed male offspring displayed reduced antioxidant glutathione peroxidase 1 () expression, increased superoxide dismutase 1 () and catalase () expression, and increased pro-oxidant NADPH oxidase activator 1 (Noxa1) expression in the adrenal glands. In addition, prenatal Dex exposure alters expression of epigenetic regulators histone deacetylase () 1, 5, 6, 7, 11, in male and in female offspring. These results suggest that glucocorticoids may mediate the fetal programming of hypertension via alteration of epigenetic machinery and oxidative stress pathways.