2025/11/08 by Basant Elsaid, Irakli Kopaliani, Birgit Zatschler +3 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Menopause: Health Impacts and Treatments #Estrogen and related hormone effects #Nitric Oxide and Endothelin Effects
paper · doi:10.1016/j.vph.2025.107559
openalex publication_date 2025/11/08 · openalex created_date 2025/11/08 · openalex updated_date 2026/08/02
Estrogen's role in cardiovascular health remains inconsistent. This study investigates the non-genomic vasorelaxant effects of 17β-estradiol, focusing on sex-specific differences in estrogen receptor (ER) subtypes (ERα, ERβ and GPER), endothelial function, and phosphoinositide 3-kinase (PI3K) pathway. Ex vivo experiments using thoracic aorta from male and female wild-type mice assessed ER expression by immunofluorescence and vascular reactivity by wire myography. Vasorelaxant responses to 17β-estradiol and ER-selective agonists (PPT, DPN and G1) were examined. Some experiments were conducted in the presence of pharmacological inhibitors targeting endothelium-dependent relaxation pathways (L-NMMA, indomethacin and apamin/charybdotoxin), as well as PI3K inhibitor LY294002. In vitro, primary mouse aortic smooth muscle cells (MASMCs) were used to assess acute effects of 17β-estradiol on myosin light chain (MLC) and Akt phosphorylation via western blot. ER subtypes were observed in the endothelial and medial regions of the vessel wall. 17β-estradiol induced similar vasorelaxation in both sexes, with subtle differences in endothelial ERβ and GPER. Nitric oxide synthase (NOS) inhibition attenuated vasorelaxation, with modest sex-specific differences in ERβ. PI3K inhibition augmented vasorelaxation regardless of endothelial integrity, exhibiting slight sex variability across ER subtypes. MASMCs showed a near-significant increase in MLC phosphorylation with 17β-estradiol, without significant Akt activation. In conclusion, estrogen induces NOS dependent vasorelaxation in mouse aorta, with no sex differences. However, subtle sex differences among ER subtypes were observed in the contribution of endothelium, NOS and PI3K pathways. The PI3K pathway may attenuate vasorelaxation by promoting MLC phosphorylation in vascular smooth muscle, and its inhibition unmasks the vasorelaxant potential of 17β-estradiol.