Background: Administration of antenatal glucocorticoids remains common practice for treating preterm delivery. Antenatal glucocorticoid exposure increased the risk of developing vascular diseases in later life, but the precise mechanisms remain unclear. This study aimed to explore the effects and mechanisms of antenatal exposure to clinically relevant doses of dexamethasone (synthetic glucocorticoids) on vascular functions in adult male offspring.
Methods: Pregnant Sprague-Dawley rats received dexamethasone or vehicle during the last week of pregnancy. Male offspring were killed at gestational day 21 (Fetus) or postnatal day 120 (adult offspring). Mesenteric arteries were collected for vascular function, electrophysiology, target gene expression, and promotor methylation studies.
Results: Antenatal dexamethasone exposure increased phenylephrine-mediated vascular contractility in offspring, which was resulted by the activated inositol 1,4,5-trisphosphate (IP3) receptor and L-type Ca2+ channels. Specifically, increases of IP3R1 (IP3 receptor 1) and Cav1.2 (L-type Ca2+ channels subunit alpha1 C) were responsible for an activated IP3-Ca2+ pathway in the vasculature, and eventually predisposed the antenatal dexamethasone offspring to vascular hypercontractility. In addition, IP3R1 and Cav1.2 was upregulated through transcriptional mechanism; the overall changes in promotor histone modifications were consistent with the corresponding changes in transcriptional levels of the 2 genes, suggesting that antenatal dexamethasone exposure activated the transcription of IP3R1 and Cav1.2 via altering promotor histone modifications.
Conclusions: Taken together, this study demonstrated that antenatal dexamethasone exposure resulted in vascular adverse outcomes in male offspring that is linked to the increases of IP3R1 and Cav1.2 mediated by epigenetic modifications in the vasculature.
Keywords: electrophysiology; gene expression; glucocorticoids; inositol; phenylephrine.