What is the relationship between Estradiol (E2) and Nitric Oxide (NO)?

From the Guidelines

Estradiol (E2) has a positive relationship with Nitric Oxide (NO) production, as it activates the endothelial nitric oxide synthase enzyme, leading to vasodilation.

Key Findings

• Estrogen, including estradiol, modulates the production of endothelium-derived factors, including nitric oxide, which plays a crucial role in vasodilation and vascular health 1.
• The activation of membrane estrogen-α of vascular endothelial cells by estetrol, a natural estrogen, contributes to nitric oxide production and vasodilation, which may prevent neointimal proliferation and hypertension 1.
• Estrogen receptors, including estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β), are expressed in cardiovascular cells and are important targets for endogenous estrogen, which promotes gene expression with a wide range of vascular effects, including regulation of vasomotor tone and response to injury 1.

Mechanisms

• The rapid, transient vasodilation that occurs within a few minutes after estrogen exposure is due to the novel ER-α–mediated activation of the endothelial nitric oxide synthase enzyme 1.
• The longer-term effects of estrogen on the vasculature, such as limiting the development of atherosclerotic lesions or vascular injury, occur over hours to days after estrogen treatment and have as their hallmark alterations in vascular gene expression 1.

Clinical Implications

• The relationship between estradiol and nitric oxide production has important implications for cardiovascular health, particularly in the context of hormone replacement therapy (HRT) and estrogen replacement therapy (ERT) 1.
• The beneficial effects of estrogen on the vasculature, including the promotion of nitric oxide production, may contribute to the protective effects of estrogen against cardiovascular disease 1.

From the Research

Relationship between Estradiol (E2) and Nitric Oxide (NO)

The relationship between Estradiol (E2) and Nitric Oxide (NO) is complex and involves multiple mechanisms. Key findings include:

• Estradiol mediates early and late endothelial nitric oxide synthase (eNOS) activation via interaction with estrogen receptors through both nongenomic and genomic mechanisms 2
• The primary physiological estrogen 17β-estradiol (E2) stimulates formation of the vasodilator nitric oxide (NO) in endothelial cells 3
• A substantial portion of E2-induced endothelium-dependent vasodilation and NO formation is mediated by the G protein-coupled estrogen receptor (GPER) 3

Mechanisms of E2-Induced NO Formation

The mechanisms of E2-induced NO formation involve:

• Activation of eNOS by E2, which requires adenosine monophosphate-dependent protein kinase (AMPK) 4
• Interaction of E2 with membrane-bound receptors, which rapidly activates intracellular signaling without binding of the hormone receptor complex to its hormone response elements 2
• Involvement of c-Src, EGFR, PI3K, and ERK signaling pathways in GPER-dependent NO formation 3

Effects of E2 on NO Production

The effects of E2 on NO production include:

• Increased eNOS catalytic activity and NO production in response to E2 4
• Improved NOx synthesis and endothelial relaxation in post-menopausal women treated with estrogen or estrogen-progesterone therapy 5
• Positive correlation between E2 and NOx concentrations in post-menopausal women 5