Rapid vascular cell responses to estrogen and membrane receptors

doi:10.1016/S0306-3623(02)00133-7

Vascular Pharmacology

Volume 38, Issue 2, February 2002, Pages 99-108

https://doi.org/10.1016/S0306-3623(02)00133-7 Get rights and content

Abstract

There is a growing interest in the effects of estrogen on the vascular wall, due to the marked gender difference in the incidence of clinically apparent coronary heart disease, when comparing premenopausal women with age-matched males. Estrogen has numerous effects on vascular endothelial and smooth muscle cells, both of which express estrogen receptors (ERs). Although ERs are classically defined as ligand-activated transcription factors, it has become increasingly clear that estrogen-stimulated, ER-dependent cellular responses can be rapid consequences of signal transduction cascades. The cellular localization and molecular form of the ER(s) which mediates rapid signaling are poorly defined. In this review, we describe the mounting evidence for membrane-localized ERs that vary in structure from classical forms. We also discuss ER-catalyzed molecular complex formations and a variety of estrogen-triggered signal transduction cascades, including those involving phosphatidylinositol 3-kinase/Akt, MAP kinase and G-protein-coupled receptors, all of which may induce “protective” profiles in vascular cells.

Introduction

The incidence of clinically significant coronary artery disease is lower in women than age-matched men, until after menopause. This epidemiology has provided support for the concept that estrogen is protective against atherosclerotic vascular disease. It is unlikely that simply the presence or absence of a threshold level of estrogen is entirely responsible for this difference; however, numerous clinical and basic research studies have demonstrated significant effects of estrogen on vascular structure and function. Clinical data regarding the potential cardiovascular benefits of estrogen replacement in postmenopausal women are currently inconclusive. Several observational studies have suggested that women receiving hormone replacement therapy (HRT) have a lower risk of heart disease. A recent update from the Nurse's health study indicated cardiovascular events decreased by 40–60% in women taking HRT (Shlipak et al., 2001). The Postmenopausal Estrogen/Progestin Interventions trial confirmed the potentially beneficial effects of estrogens on HDL and LDL cholesterol, as well as the favorable changes in some coagulation factors (fibrinogen and plasminogen). However, potentially deleterious alterations in triglycerides, factors VII and X, and antithrombin III were observed (Trial, 1995). Despite the many potentially beneficial effects of HRT on biological intermediates, the Heart Estrogen–Progestin Replacement Study showed an increase in secondary cardiovascular events in the HRT versus the placebo group during the first year of the study (Hulley et al., 1998). However, in later years, there was a decrease in cardiovascular events in the HRT group. Additionally, a retrospective population-based study of the National Registry of Myocardial Infarctions reported a 35% reduction in mortality for women who suffer a MI and were taking HRT. These studies emphasize that our knowledge of the wide array of the biological effects of estrogen is at best incomplete.

Clinical and animal studies have confirmed that estrogens have biological effects on many processes that may affect the initiation and progression of vascular diseases (see Fig. 1 and Oparil, 1999, Rossouw, 1996 for review). Our current hypothesis regarding the events that occur in the very early phases of atherogenesis is that subsequent to initial vascular injury (including lipid deposition and mechanical trauma), inflammatory responses to that injury promote the atherosclerotic cascade. These responses are accompanied by matrix deposition, vascular smooth muscle cell (SMC) migration and proliferation. Estrogen has profound effects on all of these processes.

Molecular signaling through estrogen receptors (ERs) can occur via genomic or rapid, nongenomic signaling pathways. Classically, ligand-activated ERs exert their effects through interaction with the promoter regions of a variety of genes, thus acting as transcription factors (Mangelsdorf et al., 1995). This genomic effect of estrogen requires hours to days for an increase in gene expression to occur. Nongenomic responses to estrogen occur within minutes and are intact in the presence of transcriptional inhibitors (Caulin-Glaser et al., 1997). Many of the specific effects of estrogen on the vasculature have been described in endothelial cells. Physiological concentrations of estrogen have been shown to rapidly induce endothelial nitric oxide synthase (eNOS) promoting the release of nitric oxide (NO). NO, previously called endothelium-derived relaxing factor, released from normal blood vessels results in vasodilation and is important for maintaining healthy vessels. The rapid activation of eNOS occurs in an ER-dependent, transcriptional-independent manner in the absence of cytosolic Ca²⁺ increases and requires signaling through the phosphatidyl inositol 3-kinase/Akt pathway Caulin-Glaser et al., 1997, Haynes et al., 2000. However, estrogen augmentation of NO production also proceeds through genomic mechanisms. Prolonged estrogen administration results in increased mRNA and protein expression in the human umbilical vein, bovine aortic, human aortic endothelial cells, as well as in the fetal pulmonary endothelium Hishikawa et al., 1995, MacRitchie et al., 1997. Estrogen-induced expression of eNOS can occur through the direct interaction of ER with the eNOS gene that contains multiple half-site palindromic sequences, which, together, forms a functional estrogen-response element (ERE) (Robinson et al., 1994). Interestingly, lower levels of NO were observed in ERα knockout mice (Iafrati et al., 1997). There are many positive consequences of enhanced NO release in maintaining a healthy endothelial surface. Immediately after synthesis, NO is released from the endothelial cells where it can result in vasodilation, inhibition of SMC proliferation, leukocyte adhesion and platelet aggregation Palmer et al., 1987, Radomski et al., 1990, Garg and Hasid, 1989, Kubes et al., 1991. NO activation of SMC soluble guanylate cyclase, and the resulting cGMP production mediates vascular SMC relaxation and inhibits SMC proliferation (Darkow et al., 1997). Augmented NO release is also associated with increased platelet cGMP levels and decreased aggregation Radomski et al., 1990, Radomski et al., 1987. As indicated, numerous antiatherogenic events occur as a result of enhanced eNOS enzyme activity and the concomitant increased release of NO.

The adherence of circulating leukocytes to the vascular endothelium, coupled with transendothelial migration, are important components of the athero-promoting inflammatory response. In animal models, the endothelial cell adhesion molecule (CAM) vascular cell adhesion molecule-1 (VCAM-1) is preferentially expressed by aortic endothelial cells overlying early atherosclerotic lesions (Cybulsky and Gimbrone, 1991). In cultured endothelial cells, estrogen pretreatment inhibits the interleukin-1 induced expression of VCAM-1 and E-selectin, as well as the hyperinduced expression of intercellular adhesion molecule-1 (Caulin-Glaser et al., 1996). This inhibition is specifically ER mediated through effects on transcriptional activation, including competition for critical transcription factors Caulin-Glaser et al., 1996, Harnish et al., 2000. In an animal model, reduced monocyte adherence and migration was accompanied by estrogen-induced decreased expression of VCAM-1 and attenuation of monocyte chemoattractant protein-1 expression, suggesting that estrogen plays multiple roles, blocking the adhesion of monocytes to the endothelial cell surface and inhibiting the numbers of monocytes recruited to an area of injury, as well as promoting endothelial NO release, which is, itself, antimonocyte adhesive Nathan et al., 1999, Pervin et al., 1998.

Rapid estrogen activation has been proposed to occur at the cell membrane. A few studies have demonstrated rapid induction of specific membrane-associated events. Rapid estrogen stimulation of G-proteins has been shown to induce signal transduction pathways leading to membrane channel activation and NO release Razandi et al., 1999, Wyckoff et al., 2001. In ER-transfected CHO cells, membrane K⁺ channel activation was reported to occur through rapid estrogen-stimulated activation of Gα_s and Gα_q (Razandi et al., 1999). Whereas in endothelial cells, estrogen was reported to induce the pertussis toxin sensitive G-protein α_i leading to increased NO release (Wyckoff et al., 2001). Estrogen treatment of duodenal enterocytes results in Ca²⁺ fluxes through a phospholipase C-dependent mechanism. In coronary SMC, estrogen was found to inhibit L-type Ca²⁺ channels resulting in the activation of K⁺ channels and outward K⁺ current leading to vasodilation (Ruehlmann et al., 1998). Additionally, estrogen induces the adenylate cyclase/cAMP pathway enhancing Ca²⁺ influx across L-type Ca²⁺ channels in ventricular myocytes, leading to reduced isoproterenol-stimulated augmentation in heart rate and pressure (Li et al., 2000a). It is clear from these and other studies that rapid estrogen effects can occur at the plasma membrane.

Section snippets

Signal transduction

ER is traditionally defined as a ligand-dependent transcription factor. After the binding of estrogen to ER and subsequent receptor dimerization, ER modulates the rate of gene transcription, primarily by the interaction of the DNA-binding domain (DBD) of ER with EREs in target gene promoter regions. Stimulation or repression of target gene transcription is determined by the cell and promoter specificity. However, a variety of tissues including the endothelium respond to membrane-impermeable

Variant forms of ER

The existence of a plasma membrane ER has been debated for many years and is now widely accepted. However, the molecular characteristics of the receptor are still in question. It has been claimed that various structural forms of this receptor exist, including: firstly, the putative plasma membrane ER is identical to the classical nuclear receptor; secondly, the plasma membrane ER is an alternative form of the nuclear receptor sharing common domains with classical ER; and thirdly, the plasma

Evidence that sERs are responsible for these effects

The observation that many cell types contain surface binding sites for estradiol has led to the hypothesis that these sites represent ERs whose localization, structure and/or function may differ significantly from those of the classically described nuclear ER. Specifically, we and others hypothesized that these membrane-localized receptors for estrogen might be responsible for activating many of the rapid signals described above. This is an extremely appealing idea since most rapid signaling

What is this sER?

Some debate regarding the identity of the surface ER still exists. Although it has been claimed that the membrane-localized ER is identical to the 67-kDa ERα protein identified as a DNA binding protein, we and others have described a smaller (45 kDa) protein that is recognized by anti-ERα antibodies and appears to mediate rapid signaling, but not transcriptional events, in response to estrogen. Taking advantage of an immortalized human endothelial cell line, which, under our culture conditions,

References (85)

S. Ahmad et al.
Biochem. Pharmacol.
(1999)
P. Barraille et al.
Biochem. Biophys. Res. Commun.
(1999)
D. Bar-Sagi et al.
Cell
(2000)
R. Chen et al.
J. Biol. Chem.
(2001)
G. Flores-Delgado et al.
Biochem. Biophys. Res. Commun.
(2001)
M. Frodin et al.
Mol. Cell. Endocrinol.
(1999)
K. Hisamoto et al.
J. Biol. Chem.
(2001)
K. Hishikawa et al.
FEBS Lett.
(1995)
M. Hori et al.
Pathol. Res. Pract.
(2000)
M.J. Kelly et al.
Trends Endocrinol. Metab.
(2001)

M.J. Kelly et al.

Steroids

(1999)

D.J. Mangelsdorf et al.

Cell

(1995)

M. McMahon

Methods Enzymol.

(2001)

M. Morales-Ruiz et al.

J. Biol. Chem.

(2001)

M.W. Radomski et al.

Lancet

(1987)

M. Razandi et al.

J. Biol. Chem.

(2000)

E.M. Resnick et al.

J. Biol. Chem.

(2000)

L.J. Robinson et al.

Genomics

(1994)

J.L. Wilsbacher et al.

J Biol Chem

(1999)

M.H. Wyckoff et al.

J. Biol. Chem.

(2001)

T. Caulin-Glaser et al.

J. Clin. Invest.

(1996)

T. Caulin-Glaser et al.

Circ. Res.

(1997)

K.L. Chambliss et al.

Circ. Res.

(2000)

L. Chang et al.

Nature

(2001)

M.I. Cybulsky et al.

Science

(1991)

D. Darkow et al.

Am. J. Physiol.

(1997)

S.R. Datta et al.

Genes Dev.

(1999)

S. Dimmeler et al.

Circ. Res.

(1998)

R.K. Dubey et al.

Arterioscler. Thromb. Vasc. Biol.

(2000)

W. Feng et al.

Mol. Endocrinol.

(2001)

G. Flouriot et al.

EMBO J.

(2000)

D. Fulton et al.

Nature

(1999)

U.C. Garg et al.

J. Clin. Invest.

(1989)

G.G. Geary et al.

Am. J. Physiol.

(1998)

S. Green et al.

Nature

(1986)

G.L. Greene et al.

Science

(1986)

D.C. Harnish et al.

Endocrinology

(2000)

M.P. Haynes et al.

Circ. Res.

(2000)

K. Honda et al.

J. Neurosci. Res.

(2000)

S. Hulley et al.

JAMA, J. Am. Med. Assoc.

(1998)

M.D. Iafrati et al.

Nat. Med.

(1997)

R.H. Karas et al.

Circulation

(1994)

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Rapid vascular cell responses to estrogen and membrane receptors

Abstract

Introduction

Section snippets

Signal transduction

Variant forms of ER

Evidence that sERs are responsible for these effects

What is this sER?

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Mol. Cell. Endocrinol.

J. Biol. Chem.

FEBS Lett.

Pathol. Res. Pract.

Trends Endocrinol. Metab.

Steroids

Cell

Methods Enzymol.

J. Biol. Chem.

Lancet

J. Biol. Chem.

J. Biol. Chem.

Genomics

J Biol Chem

J. Biol. Chem.

J. Clin. Invest.

Circ. Res.

Circ. Res.

Nature

Science

Am. J. Physiol.

Genes Dev.

Circ. Res.

Arterioscler. Thromb. Vasc. Biol.

Mol. Endocrinol.

EMBO J.

Nature

J. Clin. Invest.

Am. J. Physiol.

Nature

Science

Endocrinology

Circ. Res.

J. Neurosci. Res.

JAMA, J. Am. Med. Assoc.

Nat. Med.

Circulation