Gestational glucocorticoid exposure impaired endothelial nitric oxide synthesis via downregulating IP3 receptor 3 expression in male offspring vessels
Year: 2025
Type: article
Abstract: BACKGROUND: Antenatal glucocorticoid administration represents a standard therapeutic intervention for preterm birth; however, its long-term consequences on vascular endothelial function in offspring remain poorly understood. Nitric oxide (NO), the principal vasodilator secreted by vascular endothelial cells (VECs), plays a pivotal role in vascular pathophysiology when its biosynthesis is dysregulated. This investigation elucidates the effects and underlying mechanisms of gestational exposure to clinically relevant glucocorticoid doses on endothelial NO synthesis in offspring. METHODS AND RESULTS: Pregnant Sprague-Dawley rats were administered dexamethasone (DEX), a synthetic glucocorticoid, during the final gestational week. Thoracic aorta specimens from both fetal and adult offspring were isolated for experimentation. Gestational DEX exposure markedly attenuated NO-dependent acetylcholine-induced vasodilation in thoracic aorta rings from both fetal and adult male offspring. Furthermore, acetylcholine-stimulated NO synthesis was significantly impaired in VECs derived from DEX-exposed offspring thoracic aorta. Mechanistic investigations revealed that gestational DEX exposure diminished endothelial NO synthesis capacity in offspring, primarily through downregulation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) expression. Notably, gestational DEX-induced epigenetic reprogramming of IP3R3 gene expression appears to be mediated by alterations in DNA methylation status, ultimately disrupting the IP3R3/Ca 2+ /NO synthase signaling cascade in offspring VECs and predisposing to long-term vascular dysfunction through impaired NO biosynthesis. CONCLUSION: This study provides the first experimental evidence that gestational glucocorticoid exposure compromises endothelial NO synthesis in offspring vasculature through epigenetic reprogramming of IP3R3 gene expression. These novel findings demonstrate that the detrimental effects of antenatal glucocorticoid exposure on fetal vascular function persist into adulthood, offering critical insights into the developmental origins of vascular disease pathogenesis.
Source: Journal of Hypertension
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4411424306