Oxidative Stress Mediates the Fetal Programming of Hypertension by Glucocorticoids

Abstract

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 (PAH), tyrosine hydroxylase (TH), dopamine beta hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT), in a sex-specific manner. Furthermore, programmed male offspring displayed reduced antioxidant glutathione peroxidase 1 (Gpx1) expression, increased superoxide dismutase 1 (SOD1) and catalase (CAT) 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 (HDAC) 1, 5, 6, 7, 11, in male and HDAC7 in female offspring. These results suggest that glucocorticoids may mediate the fetal programming of hypertension via alteration of epigenetic machinery and oxidative stress pathways.

Novel Insights on Dietary Polyphenols for Prevention in Early-Life Origins of Hypertension: A Review Focusing on Preclinical Animal Models

“…Our understanding of the potential beneficial effects of early polyphenol supplementation to prevent hypertension of developmental origins is limited. Thus, in this review, we summarize experimental evidence documenting the use of polyphenols to prevent hypertension considering early-life interventions through pregnancy and lactation, which is presented in Table 1 [ 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. The studies are limited to those that evaluated offspring outcomes starting post-weaning.…”

“…Numerous rat models of early-life insults, such as high-fat diet [ 85 , 87 , 89 , 95 , 97 ], antenatal dexamethasone exposure [ 86 ], maternal chronic kidney disease (CKD) [ 88 ], N G -nitro-L-arginine-methyl ester (L-NAME) administration [ 90 ], prenatal asymmetric dimethylarginine (ADMA) and trimethylamine N-oxide (TMAO) exposure [ 91 ], prenatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure [ 92 ], prenatal TCDD plus dexamethasone exposure [ 93 ], maternal prenatal bisphenol A and high-fat diet exposure [ 94 ], and maternal hypertension [ 96 ], have been established to evaluate the reprogramming effects of various polyphenols on hypertension in the offspring. As shown in Table 1 , several groups of polyphenols, including flavonols [ 85 ], flavanols [ 86 , 87 ], stilbenes [ 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ], and tannins [ 97 ], have been evaluated in animal models of the early-life origins of hypertension. Among them, resveratrol is the most common polyphenol being studied [ 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ].…”

“…Since the fetus has low antioxidant capacity, overproduction of ROS under suboptimal intrauterine conditions prevails over antioxidant defenses, giving rise to oxidative stress damage and consequently fetal programming [ 107 ]. As illustrated in Table 1 , several early-life insults link oxidative stress to hypertension of developmental origins, including high-fat diet [ 85 , 95 , 97 ], antenatal dexamethasone exposure [ 86 ], maternal CKD [ 88 ], prenatal TCDD and dexamethasone exposure [ 93 ], and maternal bisphenol A and high-fat exposure [ 94 ].…”

“…In a mouse model, adult offspring of dams fed a high-fat diet during pregnancy exhibited hypertension, which was protected by quercetin supplementation in the pregnant dam [ 85 ]. Another study revealed that maternal treatment with epigallocatechin gallate attenuated the developmental programming of hypertension induced by antenatal dexamethasone administration [ 86 ].…”

Programming of Vascular Dysfunction by Maternal Stress: Immune System Implications

“…High doses of exogenous glucocorticoids have been used in experimental models to directly assess the role of glucocorticoids in triggering prenatal stress conditions. Therefore, intrauterine glucocorticoid exposure due to maternal stress conditions and exogenous glucocorticoid sources causes deleterious effects on vascular function in later life ( Lamothe et al, 2021 ) and alterations of vasoactive substances may be involved.…”