The effect of dehydroepiandrosterone on the vascular system: role of H₂S/NO pathways

Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone that serves as a precursor to androgens and estrogens and participates in several physiological processes. Its levels naturally decline with age, and reduced DHEA concentrations have been associated with an increased risk of cardiovascular disease. However, this relationship is complex, and further research is required to clarify whether DHEA supplementation may help to prevent age-related vascular dysfunction. Here, we investigated the vascular effects of DHEA using mouse aorta and bovine aortic endothelial cells (BAEC), focusing on the potential involvement of hydrogen sulfide (H₂S). DHEA exhibited a more pronounced vasorelaxant effect in endothelium intact aortas, mediated not only by nitric oxide (NO) but also by H₂S. A significant increase in H₂S production was observed following incubation of the aorta with DHEA compared to the vehicle. In addition to H₂S, the involvement of L-type calcium channels in DHEA-induced vasorelaxation was found. Nifedipine, an inhibitor of L-type calcium channels, significantly reduced DHEA-induced vasorelaxation, and vice versa, suggesting a shared target. Consistent with the aortic findings, an increase in NO formation was observed in BAEC exposed to DHEA. Using two complementary approaches, we further demonstrate that DHEA enhanced H₂S production in BAEC, with effects persisting for up to 2 h. Collectively, these findings suggest that DHEA promotes vasodilation through dual NO- and H₂S-dependent pathways, along with modulation of L-type calcium channels. Our data provide new insights into the mechanisms of action of DHEA, supporting its protective role in the vasculature.