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Experimental benefits of sex hormones on vascular function and the outcome of hormone therapy in cardiovascular disease.

Ross RL, Serock MR, Khalil RA - Curr Cardiol Rev (2008)

Bottom Line: Specific estrogen receptor modulators (SERMs) could maximize the vascular benefits, with little side effects on breast cancer.Postmenopausal decrease and genetic polymorphism in vascular ER and post-receptor signaling mechanisms could also modify the effects of HRT.Lastly, progesterone may modify the vascular effects of estrogen, and modulators of estrogen/testosterone ratio could provide alternative HRT combinations.

View Article: PubMed Central - PubMed

Affiliation: Division of Vascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Experimental data have shown beneficial vascular effects of estrogen including stimulation of endothelium-dependent nitric oxide, prostacyclin and hyperpolarizing factor-mediated vascular relaxation. However, the experimental evidence did not translate into vascular benefits of hormone replacement therapy (HRT) in postmenopausal women, and HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events with HRT. The lack of vascular benefits of HRT could be related to the hormone used, the vascular estrogen receptor (ER), and the subject's age and preexisting cardiovascular condition. Natural and phytoestrogens in small doses may be more beneficial than synthetic estrogen. Specific estrogen receptor modulators (SERMs) could maximize the vascular benefits, with little side effects on breast cancer. Transdermal estrogens avoid the first-pass liver metabolism associated with the oral route. Postmenopausal decrease and genetic polymorphism in vascular ER and post-receptor signaling mechanisms could also modify the effects of HRT. Variants of cytosolic/nuclear ER mediate transcriptional genomic effects that stimulate endothelial cell growth, but inhibit vascular smooth muscle (VSM) proliferation. Also, plasma membrane ERs trigger not only non-genomic stimulation of endothelium-dependent vascular relaxation, but also inhibition of [Ca(2+)]i, protein kinase C and Rho kinase-dependent VSM contraction. HRT could also be more effective in the perimenopausal period than in older postmenopausal women, and may prevent the development, while worsening preexisting CVD. Lastly, progesterone may modify the vascular effects of estrogen, and modulators of estrogen/testosterone ratio could provide alternative HRT combinations. Thus, the type, dose, route of administration and the timing/duration of HRT should be customized depending on the subject's age and preexisting cardiovascular condition, and thereby make it possible to translate the beneficial vascular effects of sex hormones to the outcome of HRT in postmenopausal CVD.

No MeSH data available.


Related in: MedlinePlus

Cellular mechanisms of estrogen-Induced vascular relaxation and remodeling. In endothelial cells, estrogen binds to cytosolic/ nuclear ERs, activates MAPK, and stimulates gene transcription and eNOS expression. Estrogen also binds to surface membrane ERs and stimulates Ca2+ release from the endoplasmic reticulum, the MAPK/Akt pathway, eNOS activity and NO production. NO activates guanylate cyclase (GC) and increases cGMP which causes VSM relaxation by inhibiting Ca2+ influx and stimulating Ca2+ extrusion. Estrogen’s antioxidant  effects cause decreases in NADPH and O2–• production and increases in NO bioactivity. Estrogen also activates cyclooxygenases (COX) and enhances the production of PGI2, which in turn activates adenylate cyclase (AC), increases cAMP, and causes VSM relaxation by mechanisms similar to those of cGMP. ER also increases the release of EDHF, activates K+ channels and causes VSM hyperpolarization and inhibition of Ca2+ influx via Ca2+ channels. Estrogen also activates cytosolic/nuclear ERs in VSM and inhibits growth factor (GF)-mediated activation of MAPK, gene transcription and VSM growth. Estrogen also binds to plasma membrane ERs, decrease [Ca2+]i and inhibit Ca2+- dependent MLC phosphorylation and VSM contraction. Estrogen also inhibits PKC-, MAPK- and Rho kinase and thereby leads to decreases in the myofilament force sensitivity to [Ca2+]i. Dashed arrows indicate inhibition. A: agonist, R: receptor, PLC: phospholipase C, PIP2: phospatidyinositol 4,5-bisphosphate, IP3: inositol 1,4,5-trisphosphate, DAG: diacylglycerol, SR: sarcoplasmic reticulum, CAM: calmodulin, MLC: myosin light chain, MLCK: MLC kinase, MLCP: MLC phosphatase, MEK: MAPK kinase, CaP: calponin, CaD: caldesmon.
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Figure 1: Cellular mechanisms of estrogen-Induced vascular relaxation and remodeling. In endothelial cells, estrogen binds to cytosolic/ nuclear ERs, activates MAPK, and stimulates gene transcription and eNOS expression. Estrogen also binds to surface membrane ERs and stimulates Ca2+ release from the endoplasmic reticulum, the MAPK/Akt pathway, eNOS activity and NO production. NO activates guanylate cyclase (GC) and increases cGMP which causes VSM relaxation by inhibiting Ca2+ influx and stimulating Ca2+ extrusion. Estrogen’s antioxidant effects cause decreases in NADPH and O2–• production and increases in NO bioactivity. Estrogen also activates cyclooxygenases (COX) and enhances the production of PGI2, which in turn activates adenylate cyclase (AC), increases cAMP, and causes VSM relaxation by mechanisms similar to those of cGMP. ER also increases the release of EDHF, activates K+ channels and causes VSM hyperpolarization and inhibition of Ca2+ influx via Ca2+ channels. Estrogen also activates cytosolic/nuclear ERs in VSM and inhibits growth factor (GF)-mediated activation of MAPK, gene transcription and VSM growth. Estrogen also binds to plasma membrane ERs, decrease [Ca2+]i and inhibit Ca2+- dependent MLC phosphorylation and VSM contraction. Estrogen also inhibits PKC-, MAPK- and Rho kinase and thereby leads to decreases in the myofilament force sensitivity to [Ca2+]i. Dashed arrows indicate inhibition. A: agonist, R: receptor, PLC: phospholipase C, PIP2: phospatidyinositol 4,5-bisphosphate, IP3: inositol 1,4,5-trisphosphate, DAG: diacylglycerol, SR: sarcoplasmic reticulum, CAM: calmodulin, MLC: myosin light chain, MLCK: MLC kinase, MLCP: MLC phosphatase, MEK: MAPK kinase, CaP: calponin, CaD: caldesmon.

Mentions: Estrogen induces both genomic and non-genomic effects in the vasculature. Nuclear ERs act as transcription factors that modulate gene expression by directly binding to DNA at specific estrogen response elements. ERs could also indirectly prevent transcription of promoters lacking estrogen response elements by interacting with nuclear transcription factors. ER transcriptional activity may be regulated by intracellular signaling pathways even in the absence of ER ligands [36]. Activation of cytosolic/nuclear ERs in endothelial cells triggers genomic effects leading to cell growth and proliferation. For example, 17β-estradiol (E2) induces the phosphorylation and activation of mitogen-activated protein kinase (MAPK) and proliferation of endothelial cells (Fig. 1). In contrast, E2 inhibits MAPK activity and the growth and proliferation of VSM cells [47,48]. E2 could also activate plasma membrane ERs in the endothelium and VSM, initiate non-genomic effects, and cause reduction in vasoconstriction [49].


Experimental benefits of sex hormones on vascular function and the outcome of hormone therapy in cardiovascular disease.

Ross RL, Serock MR, Khalil RA - Curr Cardiol Rev (2008)

Cellular mechanisms of estrogen-Induced vascular relaxation and remodeling. In endothelial cells, estrogen binds to cytosolic/ nuclear ERs, activates MAPK, and stimulates gene transcription and eNOS expression. Estrogen also binds to surface membrane ERs and stimulates Ca2+ release from the endoplasmic reticulum, the MAPK/Akt pathway, eNOS activity and NO production. NO activates guanylate cyclase (GC) and increases cGMP which causes VSM relaxation by inhibiting Ca2+ influx and stimulating Ca2+ extrusion. Estrogen’s antioxidant  effects cause decreases in NADPH and O2–• production and increases in NO bioactivity. Estrogen also activates cyclooxygenases (COX) and enhances the production of PGI2, which in turn activates adenylate cyclase (AC), increases cAMP, and causes VSM relaxation by mechanisms similar to those of cGMP. ER also increases the release of EDHF, activates K+ channels and causes VSM hyperpolarization and inhibition of Ca2+ influx via Ca2+ channels. Estrogen also activates cytosolic/nuclear ERs in VSM and inhibits growth factor (GF)-mediated activation of MAPK, gene transcription and VSM growth. Estrogen also binds to plasma membrane ERs, decrease [Ca2+]i and inhibit Ca2+- dependent MLC phosphorylation and VSM contraction. Estrogen also inhibits PKC-, MAPK- and Rho kinase and thereby leads to decreases in the myofilament force sensitivity to [Ca2+]i. Dashed arrows indicate inhibition. A: agonist, R: receptor, PLC: phospholipase C, PIP2: phospatidyinositol 4,5-bisphosphate, IP3: inositol 1,4,5-trisphosphate, DAG: diacylglycerol, SR: sarcoplasmic reticulum, CAM: calmodulin, MLC: myosin light chain, MLCK: MLC kinase, MLCP: MLC phosphatase, MEK: MAPK kinase, CaP: calponin, CaD: caldesmon.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2801863&req=5

Figure 1: Cellular mechanisms of estrogen-Induced vascular relaxation and remodeling. In endothelial cells, estrogen binds to cytosolic/ nuclear ERs, activates MAPK, and stimulates gene transcription and eNOS expression. Estrogen also binds to surface membrane ERs and stimulates Ca2+ release from the endoplasmic reticulum, the MAPK/Akt pathway, eNOS activity and NO production. NO activates guanylate cyclase (GC) and increases cGMP which causes VSM relaxation by inhibiting Ca2+ influx and stimulating Ca2+ extrusion. Estrogen’s antioxidant effects cause decreases in NADPH and O2–• production and increases in NO bioactivity. Estrogen also activates cyclooxygenases (COX) and enhances the production of PGI2, which in turn activates adenylate cyclase (AC), increases cAMP, and causes VSM relaxation by mechanisms similar to those of cGMP. ER also increases the release of EDHF, activates K+ channels and causes VSM hyperpolarization and inhibition of Ca2+ influx via Ca2+ channels. Estrogen also activates cytosolic/nuclear ERs in VSM and inhibits growth factor (GF)-mediated activation of MAPK, gene transcription and VSM growth. Estrogen also binds to plasma membrane ERs, decrease [Ca2+]i and inhibit Ca2+- dependent MLC phosphorylation and VSM contraction. Estrogen also inhibits PKC-, MAPK- and Rho kinase and thereby leads to decreases in the myofilament force sensitivity to [Ca2+]i. Dashed arrows indicate inhibition. A: agonist, R: receptor, PLC: phospholipase C, PIP2: phospatidyinositol 4,5-bisphosphate, IP3: inositol 1,4,5-trisphosphate, DAG: diacylglycerol, SR: sarcoplasmic reticulum, CAM: calmodulin, MLC: myosin light chain, MLCK: MLC kinase, MLCP: MLC phosphatase, MEK: MAPK kinase, CaP: calponin, CaD: caldesmon.
Mentions: Estrogen induces both genomic and non-genomic effects in the vasculature. Nuclear ERs act as transcription factors that modulate gene expression by directly binding to DNA at specific estrogen response elements. ERs could also indirectly prevent transcription of promoters lacking estrogen response elements by interacting with nuclear transcription factors. ER transcriptional activity may be regulated by intracellular signaling pathways even in the absence of ER ligands [36]. Activation of cytosolic/nuclear ERs in endothelial cells triggers genomic effects leading to cell growth and proliferation. For example, 17β-estradiol (E2) induces the phosphorylation and activation of mitogen-activated protein kinase (MAPK) and proliferation of endothelial cells (Fig. 1). In contrast, E2 inhibits MAPK activity and the growth and proliferation of VSM cells [47,48]. E2 could also activate plasma membrane ERs in the endothelium and VSM, initiate non-genomic effects, and cause reduction in vasoconstriction [49].

Bottom Line: Specific estrogen receptor modulators (SERMs) could maximize the vascular benefits, with little side effects on breast cancer.Postmenopausal decrease and genetic polymorphism in vascular ER and post-receptor signaling mechanisms could also modify the effects of HRT.Lastly, progesterone may modify the vascular effects of estrogen, and modulators of estrogen/testosterone ratio could provide alternative HRT combinations.

View Article: PubMed Central - PubMed

Affiliation: Division of Vascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Experimental data have shown beneficial vascular effects of estrogen including stimulation of endothelium-dependent nitric oxide, prostacyclin and hyperpolarizing factor-mediated vascular relaxation. However, the experimental evidence did not translate into vascular benefits of hormone replacement therapy (HRT) in postmenopausal women, and HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events with HRT. The lack of vascular benefits of HRT could be related to the hormone used, the vascular estrogen receptor (ER), and the subject's age and preexisting cardiovascular condition. Natural and phytoestrogens in small doses may be more beneficial than synthetic estrogen. Specific estrogen receptor modulators (SERMs) could maximize the vascular benefits, with little side effects on breast cancer. Transdermal estrogens avoid the first-pass liver metabolism associated with the oral route. Postmenopausal decrease and genetic polymorphism in vascular ER and post-receptor signaling mechanisms could also modify the effects of HRT. Variants of cytosolic/nuclear ER mediate transcriptional genomic effects that stimulate endothelial cell growth, but inhibit vascular smooth muscle (VSM) proliferation. Also, plasma membrane ERs trigger not only non-genomic stimulation of endothelium-dependent vascular relaxation, but also inhibition of [Ca(2+)]i, protein kinase C and Rho kinase-dependent VSM contraction. HRT could also be more effective in the perimenopausal period than in older postmenopausal women, and may prevent the development, while worsening preexisting CVD. Lastly, progesterone may modify the vascular effects of estrogen, and modulators of estrogen/testosterone ratio could provide alternative HRT combinations. Thus, the type, dose, route of administration and the timing/duration of HRT should be customized depending on the subject's age and preexisting cardiovascular condition, and thereby make it possible to translate the beneficial vascular effects of sex hormones to the outcome of HRT in postmenopausal CVD.

No MeSH data available.


Related in: MedlinePlus