Sex-Specific Regulation of Catecholamine Signaling in Rats Exposed to Dexamethasone In Utero and Angiotensin in Adulthood

Abstract

Pregnant women who are at risk of pre-term delivery are given the synthetic glucocorticoid dexamethasone (DEX) to stimulate fetal lung development as it is not degraded by 11ß-hydroxysteroid dehydrogenase, enabling DEX to freely cross through the placenta and act on the developing fetus. Our lab has previously found that in-utero DEX exposure increases stress-induced blood pressure and heart rate responses in female, as well as autonomic dysregulation in the adult offspring. Angiotensin II (Ang II) induces hypertension and cardiac remodeling in part through activation of the sympathetic nervous system. Given these prior findings, this project explores whether prenatal DEX exposure alters the response of Ang II on cardiac sympathetic nervous system regulation. Pregnant rats were administered either vehicle (20% w/v 2-hydroxypropyl ß-cyclodextran) or the glucocorticoid DEX (0.4 mg/kg body weight, i.p) on gestation days 18-21. When offspring reached ~15 weeks of age, groups were administered either subcutaneous AngII (200 ng/kg per min) as a cardiovascular challenge or saline as experimental control for four weeks. To measure local sympathetic signaling, tyrosine hydroxylase (TH) was analyzed as it serves as the rate limiting step of catecholamine synthesis while catechol-O-methyltransferase (COMT) was selected as it catalyzes catecholamine breakdown. Gene expression of adrenoreceptor ß1 ( Adrb1) was measured to assess receptor availability for sympathetic activity. Data were analyzed by 3-way ANOVA with sex, prenatal treatment (i.e., DEX vs. Vehicle), and postnatal treatment (i.e., saline vs. AngII) as the variables. There was an overall main effect of prenatal DEX treatment to reduce TH expression in the LV (p=0.018), an effect that was more pronounced in males. COMT expression was found to be significantly impacted by sex, prenatal treatment, and post-natal treatment (3-way interaction, p=0.016). Thus, the degree to which DEX and Ang II impacted COMT expression differed by sex. There was a sex x postnatal treatment interaction (p=0.013) on ADRB1 expression whereby expression was increased by Ang II only in female hearts. Although prior studies have shown that Ang II can increase local sympathetic activity in the heart, the present data suggest that prenatal treatments disrupt this response in a sex-specific manner. Moreover, sex and prenatal treatment were greater drivers of local sympathetic regulation than Ang II. NIMH/ORWH 1U54MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.