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Vascular Aging in Women: is Estrogen the Fountain of Youth?

Novella S, Dantas AP, Segarra G, Medina P, Hermenegildo C - Front Physiol (2012)

Bottom Line: Experimental and some clinical studies have attributed most of the protective effects of estrogen to its modulatory action on vascular endothelium.The thromboxane A(2) pathway is key to regulating vascular tone in females.We aim to clarify how menopause and aging contribute jointly to vascular aging and how estrogen modulates vascular response at different ages.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Fisiología, Universitat de València Valencia, Spain.

ABSTRACT
Aging is associated with structural and functional changes in the vasculature, including endothelial dysfunction, arterial stiffening and remodeling, impaired angiogenesis, and defective vascular repair, and with increased prevalence of atherosclerosis. Cardiovascular risk is similar for older men and women, but lower in women during their fertile years. This age- and sex-related difference points to estrogen as a protective factor because menopause is marked by the loss of endogenous estrogen production. Experimental and some clinical studies have attributed most of the protective effects of estrogen to its modulatory action on vascular endothelium. Estrogen promotes endothelial-derived NO production through increased expression and activity of endothelial nitric oxide synthase, and modulates prostacyclin and thromboxane A(2) release. The thromboxane A(2) pathway is key to regulating vascular tone in females. Despite all the experimental evidence, some clinical trials have reported no cardiovascular benefit from estrogen replacement therapy in older postmenopausal women. The "Timing Hypothesis," which states that estrogen-mediated vascular benefits occur only before the detrimental effects of aging are established in the vasculature, offers a possible explanation for these discrepancies. Nevertheless, a gap remains in current knowledge of cardiovascular aging mechanisms in women. This review comprises clinical and experimental data on the effects of aging, estrogens, and hormone replacement therapy on vascular function of females. We aim to clarify how menopause and aging contribute jointly to vascular aging and how estrogen modulates vascular response at different ages.

No MeSH data available.


Related in: MedlinePlus

Dual effects of estradiol (E2) on eNOS expression and activity. Estradiol effects on eNOS-mediated nitric oxide (NO) production include both genomic and non-genomic effects. Genomic effects include the classical intracellular estrogen receptors (ER), which after binding of E2 interact with estrogen-response element (ERE) in DNA, resulting in an increased eNOS expression. Moreover, E2 binding to GPER leads to activation of different transcriptional factors such as cAMP response element (CRE) which also induces eNOS expression. Among non-genomic effects, ER and GPER regulate the E2-induced eNOS activity (modified from Sobrino, 2011).
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Figure 1: Dual effects of estradiol (E2) on eNOS expression and activity. Estradiol effects on eNOS-mediated nitric oxide (NO) production include both genomic and non-genomic effects. Genomic effects include the classical intracellular estrogen receptors (ER), which after binding of E2 interact with estrogen-response element (ERE) in DNA, resulting in an increased eNOS expression. Moreover, E2 binding to GPER leads to activation of different transcriptional factors such as cAMP response element (CRE) which also induces eNOS expression. Among non-genomic effects, ER and GPER regulate the E2-induced eNOS activity (modified from Sobrino, 2011).

Mentions: The vascular protection conferred by estrogen may be mediated indirectly by its influence on the metabolism of lipoproteins or by a direct action on the modulation of molecular pathways in the vessel wall, and more specifically on endothelial cells (Hermenegildo et al., 2002). Vascular endothelium not only regulates vascular tone through flow-mediated mechanisms, but also confers antithrombotic and antiinflammatory properties to the blood vessel. Nitric oxide (NO), the primary endothelial-derived mediator, is involved in many physiological processes, including vasodilation and inhibition of thrombosis, cell migration, and proliferation (Dudzinski and Michel, 2007; Lamas et al., 2007; Michel and Vanhoutte, 2010). Estrogen is known to increase NO bioavailability by mechanisms that either directly increase NO generation (Figure 1) or decrease superoxide anion concentration, thereby attenuating -mediated NO inactivation. Mechanisms involved in estrogen-induced increases in NO availability include: (1) transcriptional stimulation of endothelial NO synthase (eNOS) gene expression (Huang et al., 1997; Sumi and Ignarro, 2003); (2) non-genomic activation of enzyme activity via a PI3K/phosphokinase B (PKB/AKT)-mediated signaling pathway (Hisamoto et al., 2001); (3) increased intracellular free Ca2+ concentration ([Ca2+]i) in endothelial cells (Rubio-Gayosso et al., 2000); (4) decreased production of asymmetric dimethylarginine (ADMA), the eNOS endogenous inhibitor (Monsalve et al., 2007); and (5) attenuated concentrations (Wassmann et al., 2001; Dantas et al., 2002; Ospina et al., 2002).


Vascular Aging in Women: is Estrogen the Fountain of Youth?

Novella S, Dantas AP, Segarra G, Medina P, Hermenegildo C - Front Physiol (2012)

Dual effects of estradiol (E2) on eNOS expression and activity. Estradiol effects on eNOS-mediated nitric oxide (NO) production include both genomic and non-genomic effects. Genomic effects include the classical intracellular estrogen receptors (ER), which after binding of E2 interact with estrogen-response element (ERE) in DNA, resulting in an increased eNOS expression. Moreover, E2 binding to GPER leads to activation of different transcriptional factors such as cAMP response element (CRE) which also induces eNOS expression. Among non-genomic effects, ER and GPER regulate the E2-induced eNOS activity (modified from Sobrino, 2011).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368545&req=5

Figure 1: Dual effects of estradiol (E2) on eNOS expression and activity. Estradiol effects on eNOS-mediated nitric oxide (NO) production include both genomic and non-genomic effects. Genomic effects include the classical intracellular estrogen receptors (ER), which after binding of E2 interact with estrogen-response element (ERE) in DNA, resulting in an increased eNOS expression. Moreover, E2 binding to GPER leads to activation of different transcriptional factors such as cAMP response element (CRE) which also induces eNOS expression. Among non-genomic effects, ER and GPER regulate the E2-induced eNOS activity (modified from Sobrino, 2011).
Mentions: The vascular protection conferred by estrogen may be mediated indirectly by its influence on the metabolism of lipoproteins or by a direct action on the modulation of molecular pathways in the vessel wall, and more specifically on endothelial cells (Hermenegildo et al., 2002). Vascular endothelium not only regulates vascular tone through flow-mediated mechanisms, but also confers antithrombotic and antiinflammatory properties to the blood vessel. Nitric oxide (NO), the primary endothelial-derived mediator, is involved in many physiological processes, including vasodilation and inhibition of thrombosis, cell migration, and proliferation (Dudzinski and Michel, 2007; Lamas et al., 2007; Michel and Vanhoutte, 2010). Estrogen is known to increase NO bioavailability by mechanisms that either directly increase NO generation (Figure 1) or decrease superoxide anion concentration, thereby attenuating -mediated NO inactivation. Mechanisms involved in estrogen-induced increases in NO availability include: (1) transcriptional stimulation of endothelial NO synthase (eNOS) gene expression (Huang et al., 1997; Sumi and Ignarro, 2003); (2) non-genomic activation of enzyme activity via a PI3K/phosphokinase B (PKB/AKT)-mediated signaling pathway (Hisamoto et al., 2001); (3) increased intracellular free Ca2+ concentration ([Ca2+]i) in endothelial cells (Rubio-Gayosso et al., 2000); (4) decreased production of asymmetric dimethylarginine (ADMA), the eNOS endogenous inhibitor (Monsalve et al., 2007); and (5) attenuated concentrations (Wassmann et al., 2001; Dantas et al., 2002; Ospina et al., 2002).

Bottom Line: Experimental and some clinical studies have attributed most of the protective effects of estrogen to its modulatory action on vascular endothelium.The thromboxane A(2) pathway is key to regulating vascular tone in females.We aim to clarify how menopause and aging contribute jointly to vascular aging and how estrogen modulates vascular response at different ages.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Fisiología, Universitat de València Valencia, Spain.

ABSTRACT
Aging is associated with structural and functional changes in the vasculature, including endothelial dysfunction, arterial stiffening and remodeling, impaired angiogenesis, and defective vascular repair, and with increased prevalence of atherosclerosis. Cardiovascular risk is similar for older men and women, but lower in women during their fertile years. This age- and sex-related difference points to estrogen as a protective factor because menopause is marked by the loss of endogenous estrogen production. Experimental and some clinical studies have attributed most of the protective effects of estrogen to its modulatory action on vascular endothelium. Estrogen promotes endothelial-derived NO production through increased expression and activity of endothelial nitric oxide synthase, and modulates prostacyclin and thromboxane A(2) release. The thromboxane A(2) pathway is key to regulating vascular tone in females. Despite all the experimental evidence, some clinical trials have reported no cardiovascular benefit from estrogen replacement therapy in older postmenopausal women. The "Timing Hypothesis," which states that estrogen-mediated vascular benefits occur only before the detrimental effects of aging are established in the vasculature, offers a possible explanation for these discrepancies. Nevertheless, a gap remains in current knowledge of cardiovascular aging mechanisms in women. This review comprises clinical and experimental data on the effects of aging, estrogens, and hormone replacement therapy on vascular function of females. We aim to clarify how menopause and aging contribute jointly to vascular aging and how estrogen modulates vascular response at different ages.

No MeSH data available.


Related in: MedlinePlus