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(Circulation Research. 2006;99:459.)
© 2006 American Heart Association, Inc.

Editorials

Estrogen and Different Aspects of Vascular Disease in Women and Men

Carl J. Pepine, Wilmer W. Nichols, Daniel F. Pauly

From the Division of Cardiovascular Medicine, University of Florida College of Medicine

Correspondence to Carl J. Pepine, MD, Division of Cardiovascular Medicine, University of Florida College of Medicine, 1600 SW Archer Road/Box 100277, Gainesville, FL 32610-0277. E-mail pepincj{at}medicine.ufl.edu

See related article, pages 477–484

Key Words: estrogen receptor-alpha (ESR1) • estrogen receptor-alpha genotype (ESR1) • gender-related vascular disease • women and vascular disease • men and vascular disease • vascular structure and function

	Introduction

Top Introduction Differences in Vascular Disease... Clinical Characteristics and... Estrogen and Sex/Gender-Related... References

 
Considerable evidence indicates that sex hormones have an important influence on cardiovascular physiology and pathology.^1,2 Recent work suggests that a mechanism based on estrogen receptor-alpha (ESR1) contributes to a range of structural and functional responses that relate to vascular disease. Most of this work focuses on ESR1 activity within the endothelium and yields variable findings due, at least in part, to differences in the vascular bed or species studied, as well as other experimental conditions such as age, estrogen status, degree of preconstriction, etc. But many findings in conduit arteries (eg, more frequent plaque erosion, increased wall stiffness, spasm, etc) and microvessels (eg, reduced coronary flow reserve, hot flashes, etc) implicate smooth muscle cells (SMCs) in gender differences in vascular disease. These cells are directly responsible for extracellular matrix production and assure the integrity of the artery wall. They may be decreased, apoptotic, or dysfunctional in terms of synthesis and repair of extracellular matrix, which is destroyed in vulnerable plaque by macrophages.

In this issue of Circulation Research Montague and colleagues³ report that activation of ESR1 decreases human aorta SMC differentiation (Figure). Importantly, they found that SMCs of men, compared with women, had reduced ESR1 expression associated with increased differentiation markers. Their work suggests that ESR1 activation switches SMC to a form that may promote plaque vulnerability. Could different activational states of ESR1 be responsible for shifting the functional characteristics of SMCs toward a phenotype that explains some complexities of gender-related differences in vascular disease?

View larger version (18K): [in this window] [in a new window]   Hypothetical construct based on Montague et al suggests that the activational state of estrogen receptor-alpha (ESR1) governs the vascular smooth muscle (SMC) phenotype. Among men with lower ESR1 expression they identified higher levels of differentiation markers compared with women. However activation of ESR1 in SMCs containing low ESR1 expression reduced differentiation markers and promoted apoptosis. This was accomplished by the authors using lentivirus transduction. Conversely, inhibiting ESR1 in SMCs expressing high levels of interfering RNA (SiRNA). The balance between these mechanisms could contribute to vascular remodeling and plaque instability.

	Differences in Vascular Disease Between Women and Men

Top Introduction Differences in Vascular Disease... Clinical Characteristics and... Estrogen and Sex/Gender-Related... References

 
Risk conditions and clinical findings indicate that the pathophysiology underlying ischemic vascular disease differs between women and men.⁴ A number of conditions are unique to women (eg, early age at menopause, hypertensive disorders of pregnancy, gestational diabetes, peripartum aortic or coronary dissection, polycystic ovarian syndrome, hypothalamic hypoestrogenemia, etc). Other factors linked with vascular disease or dysfunction are much more frequent in women than men (eg, migraine, coronary spasm, vasculitis, Raynaud phenomenon, etc). On this background, postmenopausal women more frequently have many traditional vascular disease risk conditions (eg, diabetes, obesity, hypertension, inactivity, etc) which occur and cluster more frequently in women than men. In addition to this greater burden of risk factors, the woman with vascular disease often is older and has more functional disability than her male counterpart.^5,6 Women have poor clinical outcomes compared with men with acute coronary syndromes,⁷ chronic coronary syndromes,⁸ coronary revascularization,⁹ and heart failure¹⁰ that cannot be explained by simply adjusting for age. So other factors must contribute to the increased severity of vascular disease in women compared with men.

	Clinical Characteristics and Links With Sex Hormones

Top Introduction Differences in Vascular Disease... Clinical Characteristics and... Estrogen and Sex/Gender-Related... References

 
Although, ischemic vascular disease is the most frequent cause of death for women, its prevalence in women compared with men does not increase markedly until after menopause when major changes in sex hormones occur. During menopause estrogen levels are about one-tenth premenopausal levels and the predominant source, estradiol, changes to estrone produced by conversion of androgens in adipose tissue.^1,6 Age-dependent aromatase expression in SMCs provides a mechanism for local production of estrogens from androgens.¹¹ Aging attenuates many estrogen-related potentially beneficial responses.¹² Yet, we have observed that central-induced endogenous estrogen deficiency in younger women is associated with a >7-fold increase in risk of coronary obstruction.¹³ One interpretation is the widely varying estrogen/androgen balance occurring throughout a woman’s life contributes to differences in vascular disease compared with men. This includes high levels of estrogen premenopause and decreasing estrogen and progesterone levels postmenopause, along with changing hormone balance during pregnancy, peripartum, and oral contraceptive or replacement therapy. Such varying estrogen/androgen balance interacts with the female unique and traditional risk conditions, as well as diet (eg, phytoestrogens, etc), physical activity, psychosocial characteristics, etc, to modulate differences in vascular disease.

Estrogen exerts effects via 2 receptors abundant in vascular tissue to transduce signals regulating expression of many genes, and it also has nongenomic effects.¹ Considerable evidence implicates the ESR1 in vascular structure and function. Attempts to link estrogen receptor-alpha gene (ESR1) variation with adverse outcomes yield mixed results.^14–19 Recently an overview of 5 studies including >7000 men suggested a 44% excess risk of myocardial infarction associated with the CC genotype at ESR1 c454–397T>C,²⁰ strengthening the finding of an almost 2-fold increased risk of stroke associated with this CC genotype among 2709 of these men.²¹ Yet a study in 3404 postmenopausal women provided no evidence for an association of ESR1 genotypes or haplotypes with vascular outcomes.²² In light of Montague and colleagues’³ work, could variation in activation of ESR1 and changes in SMCs explain this link with vascular outcomes among men but not women? Clearly a better understanding is needed of the characteristics of SMCs of women and men among various phenotypes of ischemic vascular disease or ideally even before vascular disease becomes clinically apparent.

	Estrogen and Sex/Gender-Related Differences in Blood Vessels

Top Introduction Differences in Vascular Disease... Clinical Characteristics and... Estrogen and Sex/Gender-Related... References

 
Women have smaller and stiffer conduit arteries than men even when adjusted for height, weight, and arterial pressure,^23,24 contributing to earlier return of reflected arterial pulse waves, widened pulse pressure, and adverse effects on myocardial oxygen supply and demand. We found brachial pulse pressure to be the best independent predictor of cardiovascular adverse outcomes among blood pressure measures,²⁵ suggesting that elastic properties of conduit arteries are important in the vasculopathy of women.

Changes in artery size (eg, remodeling) may occur in response to physiologic (eg, pregnancy, exercise, etc) or pathologic (eg, atherosclerosis, hypertension, etc) stimuli. Insight into potentially pathologic gender-related differences in remodeling comes from cardiac transplant recipients and transgender patients. Female hearts transplanted to females show little change in coronary size over time.²⁶ But female hearts transplanted to males show progressive coronary enlargement, independent of body size and left ventricular hypertrophy, that persist over time. Links between sex hormones and differences in arterial size are strengthened by studies of transsexuals where brachial artery size in genetic males taking estrogens is smaller compared with control males.^27,28 Genetic females taking androgens have larger arteries than control females.²⁹ Androgen-deprivation therapy in genetic males is associated with smaller brachial artery size compared with control males.³⁰ These findings support the notion that sex hormone balance has different, and under certain circumstances opposite, effects on conduit artery remodeling with an androgen state causing positive remodeling compared with an estrogen state. Positive remodeling is not invariably a compensating response and is also a marker of vascular disease.³¹ Positive remodeling as a marker for plaque vulnerable to rupture or erosion could be linked with the high event rate observed among women with normal or non-obstructive coronary angiographic findings.^32–34

The findings of Montague et al³ of differential effects of ESR1 activation on SMC function advance our understanding the role of estrogen in regulation of vascular physiology and pathology. These findings should shed light on the complexities of gender-related vascular disease.

	Acknowledgments

 
Sources of Funding

This work was supported by contracts from the National Heart, Lung, and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, a GCRC grant MO1-RR00425 from the National Center for Research Resources, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, California, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania, and QMED, Inc, Laurence Harbor, New Jersey.

Disclosures

None.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Differences in Vascular Disease... Clinical Characteristics and... Estrogen and Sex/Gender-Related... References

 

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