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Ann Thorac Surg 1998;65:868-874
© 1998 The Society of Thoracic Surgeons

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Current Review

The Biology of Estrogen-Mediated Repair of Cardiovascular Injury

Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA

Dr Selzman, Department of Surgery, University of Colorado Health Sciences Center, Campus Box C-320, 4200 East Ninth Ave, Denver, CO 80262 (e-mail: selzman_c@defiance.uchsc.edu).

	Abstract

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
Women appear to be protected from cardiovascular disease until the onset of menopause. Considerable evidence supports the atheroprotective effects of endogenous and supplemental estrogens. The beneficial effects of estrogens on lipid metabolism cannot wholly explain this phenomenon. Accumulating data suggest that estrogen may act at the cellular and molecular level to influence atherogenesis. The purpose of this review is to examine lipid-independent mechanisms of estrogen-mediated atheroprotection after cardiovascular injury.

	Introduction

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
The premise that atherogenesis represents an exaggerated inflammatory, fibroproliferative response to injury has evolved into an attractive unifying hypothesis of vascular disease and repair [1]. Briefly, a host of mechanical, metabolic, and toxic insults may injure the vessel wall. These include hypertension, viruses, nicotine, homocysteine, oxidized low-density lipoproteins, angioplasty catheters, and foreign bodies. The disruption of the endothelium not only results in endothelial cell dysfunction, but also allows for the adhesion and transmigration of circulating monocytes, platelets, and T lymphocytes. Within the developing thrombus and plaque, these activated cells release potent growth-regulatory molecules that may act in both a paracrine and autocrine manner. Under the influence of multiple cytokines and growth factors, smooth muscle cells (SMCs) adapt to a synthetic phenotype and commence proliferation and migration across the internal elastic lamina into the intimal layer. Stimulated SMCs allow for the deposition of extracellular matrix (ECM), thus converting the initial lesion to a fibrous plaque. Theoretically, each stage is reversible and may serve as a therapeutic target (Fig 1).

View larger version (42K): [in this window] [in a new window]   The response to injury hypothesis. (EC = endothelial cells; IEL = internal elastic lamina; PMNs = polymorphonuclear neutrophils; SMC = smooth muscle cells.)

Although lipid-lowering therapies might achieve cardiovascular benefits similar to those of estrogen therapy, these alterations are unlikely to be the sole mechanism of estrogen-mediated cardioprotection. Analysis of the Lipid Research Clinic Follow-up Study suggests that the lipid-modifying effects of estrogen were unable to account for the observed reduction in cardiovascular deaths in the estrogen users group [3]. The purpose of this review is to examine the lipid-independent atheroprotective effects of estrogen within the response to injury paradigm. The diverse nature of estrogen activity may permit targeted therapies at several levels of postinjury atherogenesis.

	Estrogens and Cardiovascular Surgery

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
Cardiovascular surgeons have long used conjugated estrogens to reduce blood loss associated with open heart procedures. Although Ambrus and colleagues [4] demonstrated significant reduction in blood loss with preoperative and intraoperative administration of conjugated estrogens, a more recent study suggests that conjugated estrogen treatment has no effect on bypass-associated hemorrhage [5]. Unfortunately, the latter study only looked at male patients, who generally possess inactive estrogen receptors. Although there are no strong data, conjugated estrogens may offer a therapeutic avenue to prevent excessive blood loss in women undergoing open heart operations.

The majority of studies examining estrogen-mediated atheroprotection can be categorized according to the respective methods of provoking experimental atherosclerosis: dietary manipulation, immunologic perturbations, and direct endothelial injury. Atherogenic diets composed of various concentrations of cholesterol and other lipids have historically been accepted as a method of atherosclerosis research. In 1951, Pick and associates [6] first observed a decrease in visible coronary atherosclerosis in a cholesterol-fed chicken given estrogens. Subsequent studies corroborated this observation in several vascular territories and attributed lesion regression to the hypolipidemic effects of the hormone [7]. Attempting to implicate nonlipid effects of estrogens, other investigators have reported inhibition of atherosclerosis without changes in serum cholesterol and lipoprotein levels [8]. However, these results are difficult to interpret because both control and experimental animals exhibited elevated lipid profiles. Dietary exacerbation of atherosclerosis is predicated on supraphysiologic lipid-concentrated diets for periods of months to years. Thus, the relationship between the lesions of cholesterol-fed animals and humans may, in some instances, be different. We recently demonstrated that ovariectomized ewes, on a standard range diet, had development of aortic intimal hyperplasia that was abrogated by hormonal replacement independent of changes in serum lipids (unpublished data). These findings suggest that the nonlipid effects of estrogens are important in vascular remodeling.

The most common cause of repeat cardiac transplantation is the development of graft atherosclerosis. Indeed, organ transplantation provides an immunologically mediated smoldering inflammation provoking intimal hyperplasia. In cholesterol-fed rabbits, estrogen protected against coronary atherosclerosis 6 weeks after cardiac transplantation [9]. Similarly, Cheng and colleagues [10] reported a decrease in intimal hyperplasia after aortic allograft to cholesterol-fed rabbit carotid arteries. Cheng and colleagues implicated estrogen-mediated inhibition of macrophage infiltration as a possible explanation. In cardiac allografts, estrogens not only decreased macrophage infiltration, but also abolished major histocompatability complex class II antigen expression [11]. No human trials exist, yet this experimental evidence suggests that estrogens may be useful in preventing graft atherosclerosis in the female cardiac transplant patient.

Injury models of atherosclerosis are premised on direct endothelial and medial damage to the blood vessel wall with a subsequent inflammatory response to the injury. These models are relevant to restenosis after angioplasty and surgical anastomoses. Rhee and coworkers [12] demonstrated that estradiol inhibited the development of intimal thickening after transection and reanastomosis of rabbit abdominal aortas. Estrogens have suppressed intimal hyperplasia after balloon injury in both the aortoiliac and carotid territories [13]. These laboratory results correlate with recent human trials. Postmenopausal women receiving HRT demonstrated reduced angiographic measures of restenosis and survival after coronary angioplasty [14]. Additionally, Sullivan and colleagues [15] monitored 1098 women after coronary bypass grafting (92 women received HRT). At 10 years, survival was 81% in the HRT group and 65% in the nonuser group (p = 0.0001). Women receiving HRT had fewer vessels with significant stenosis, higher ejection fractions, and fewer prior episodes of myocardial infarction [15]. This study suggests that estrogens not only can prevent coronary disease, but can improve survival in women with existing coronary disease, especially after coronary revascularization.

	Estrogens and Endothelium

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
The vascular endothelium represents the first line of defense and is crucial to the homeostatic regulation of the response to injury. In its quiescent state, this monolayer serves as a strategic barrier between blood and the vessel wall, maintaining the fluidity of blood flow and attenuating the risk of luminal thrombosis. However, the endothelium is more than a structural boundary; it is capable of diverse metabolic and regulatory functions. The endothelium exerts its influence over blood vessel tone, permeability, leukocyte adhesion, coagulation, and growth by balancing its responses to signals of proinflammatory and antiinflammatory circulating molecules.

The presence of an intact endothelium mitigates the neointimal response after balloon injury. As such, one possible mechanism of estrogen’s atheroprotection might be the hormone’s ability to restore the integrity of damaged endothelium. Reendothelialization after balloon injury in carotid arteries of rats receiving estrogens has been observed [16]; however, similar in vitro findings have been inconclusive. Although some investigators have demonstrated enhanced endothelial growth, evidence from our laboratory and others suggests that estrogens at physiologic doses do not promote endothelial cell proliferation [17]. Recent evidence suggests that estrogens may prevent tumor necrosis factor-induced apoptosis, or programmed cell death, in human umbilical vein endothelial cells [18]. The resultant maintenance of structural integrity allows for preservation of the functional capacity of the endothelium after noxious stimuli.

Estrogens and Prostaglandins
Prostacyclin is an endogenous vasodilator and inhibitor of platelet aggregation that is produced in endothelial cells as a breakdown product of arachadonic acid by cyclooxygenase and prostacyclin synthase (Fig 2). Prostacyclin is rapidly metabolized in the plasma to the inactive but stable 6-keto-prostaglandin F₁. Investigators have offered conflicting reports about the effect of estrogens on prostaglandin synthesis. The paradigm of estrogens and atherosclerosis might suggest that the hormone augments production of this antithrombotic molecule. Steinleitner and colleagues [19] demonstrated increased levels of 6-keto-prostaglandin₁ in human uterine arteries from premenopausal, but not postmenopausal, women. These findings in humans have been corroborated by data in cholesterol-fed rabbits [20], as well as in tissue culture [21]. However, evidence also suggests that estrogens may decrease prostacyclin production. When men undergoing coronary bypass grafting were given preoperative conjugated equine estrogens, Hull and associates [5] found a decrease in prostacyclin production from saphenous vein grafts. This clinical observation is supported experimentally in culture, but some authors criticize the techniques involved with static in vitro studies. Redmond and colleagues [22] underscored the importance of using dynamic systems in studies of endothelial function. Recently, they demonstrated decreased hypoxia- and flow-induced prostacyclin release in endocardial endothelial cells treated with estrogen [22].

View larger version (25K): [in this window] [in a new window]   Endothelial production and metabolism of nitric oxide (NO) and prostacyclin (PGI2). (Ach = acetylcholine; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; cNOS = constitutive NO synthase; iNOS = inducible NO synthase; PLA2 = phospholipase A2; 6-keto-PGF1 = 6-keto-prostaglandin F1.)

Nitric oxide is produced in the endothelial cytoplasm from the substrate L-arginine, which is governed by the constitutive enzyme NO synthase. Additionally, NO production can be dramatically augmented by the induction of inducible NO synthase after exposure of the cells to cytokines or bacterial products (see Fig 2). Nitric oxide promotes vasodilation by increasing levels of cyclic guanosine monophosphate, thereby opening calcium-sensitive potassium channels with resultant membrane hyperpolarization and decreased pressure-induced constriction. Both NO donors and NO antagonists have been used to document the beneficial relationship between NO, estrogens, and vasorelaxation [27]. The effect of estrogen on vascular smooth muscle NO production is unknown. As such, estrogen-mediated vasorelaxation is thought to be a paracrine phenomenon originating from the endothelium. Indeed, estrogens upregulate expression of constitutive NO synthase in human umbilical vein endothelial cells and human aortic endothelial cells [28]. This effect is abrogated with both tamoxifen and the pure estrogen receptor antagonist ICI 182,780.

	Estrogens and Leukocyte Adhesion

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
At sites of endothelial injury, circulating monocytes, neutrophils, platelets, and lymphocytes congregate to initiate the inflammatory process. These interactions are characterized by a diverse system of adhesion molecules and receptors on both the endothelial and inflammatory cell (Table 1). The integrins are transmembrane glycoproteins that mediate interactions between cells and ECM. The ß₁ subfamily, initially designated as VLA (very late after) antigens, links cells with the ECM and plays a crucial role in tissue organization, position, differentiation, inflammation, and growth. The most clinically relevant, ß₂ integrins share a common ß-chain (CD18), are restricted to leukocytes, and are central to firm leukocyte–endothelial adhesion. The immunoglobulin superfamily are cell-surface proteins involved with antigen recognition, complement binding, and cellular adhesion. Intracellular cell adhesion molecule-1 (ICAM-1) and its interaction with the ß₂ integrins are the best described. Endothelial upregulation of ICAM-1 occurs after exposure to soluble mediators of inflammation, including tumor necrosis factor (TNF), interleukin-1 (IL-1), and lipopolysaccharide. The selectin family is responsible for the initial leukocyte adhesive event including rolling and emigration. E-selectin (ELAM) is not constitutively expressed by the endothelium, but after stimulation from several inflammatory mediators, appears within 60 minutes, peaking after 4 to 6 hours. Similar stimulation causes a rapid exocytosis of P-selectin stored in endothelial cell Weibel-Palade bodies and shedding of L-selectin by leukocytes. The three selectins form ligands with both protein and carbohydrate moieties, the latter well represented by the fucosylated tetrasaccharide, sialyl Lewis X (SLe^x).

In vitro, Cid and colleagues [31] demonstrated that TNF, but not IL-1 or IL-4, induced adhesion of neutrophils to human umbilical vein endothelial cells after concomitant addition of estradiol. This increased adhesion was partially blocked with antibodies to ELAM-1, ICAM-1, and VCAM-1. Additionally, indirect immunofluorescence demonstrated upregulation of these molecules with estrogen and TNF treatment [31]. Similarly, Aziz and Wakefield [32] demonstrated a significant increase in ELAM-1 after 6 hours of TNF and estradiol stimulation. However, the upregulation of ELAM was not observed at 23 hours, and estradiol had no effect on ICAM-1 or VCAM-1 expression after TNF or IL-1 stimulation at either 6 or 23 hours. These authors concluded that estrogen promotion of leukocyte–endothelial interactions might contribute to the predominance of autoimmune inflammatory disease in women. These two studies are similar in both methods and conclusions. Both simultaneously delivered estradiol and stimulant (TNF or IL-1) to the culture system. If estradiol is to act through receptor-mediated events, it might not be able to compete concomitantly with cytokines for transcriptional machinery, perhaps masking the true effect of the hormone. This potential problem is addressed in two additional in vitro experiments. Nakai and associates [33] observed that human umbilical vein endothelial cells preincubated with 17ß-estradiol for 24 hours were able to suppress the induction of VCAM-1 mRNA expression after IL-1ß stimulation. Similarly, Caulin-Glaser and coworkers [34] demonstrated a 60% to 80% decrease in ELAM-1, VCAM-1, and ICAM-1 expression after IL-1 stimulation of human umbilical vein endothelial cells preincubated with estradiol. Furthermore, the estrogen receptor was directly implicated in this downregulation as the pure estrogen receptor antagonist ICI 164,384 abrogated this reduction [34].

	Estrogens, Cytokines, and Growth Factors

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
On adhering to the endothelium, monocytes migrate into the vessel wall where they undergo transformation into tissue macrophages. Along with adherent lymphocytes, platelets, and local endothelial cells and SMCs, the activated macrophage is capable of producing a wide variety of cytokines and growth factors that may participate in atheroma progression. These proteins act in paracrine, autocrine, and juxtacrine fashion on the vessel wall to promote endothelial dysfunction, leukocyte adhesion, thrombus formation, and proliferation of smooth muscle (Fig 3).

View larger version (27K): [in this window] [in a new window]   Growth factor and cytokine relationships important in atherogenesis. (EC = endothelial cell; EGF = epidermal growth factor; FGF = fibroblast growth factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; IFN = interferon; IGF = insulin-like growth factor; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MCP-1 = monocyte chemotaxic protein; PDGF = platelet-derived growth factor; SMC = smooth muscle cell; TGF = transforming growth factor; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor.)

Cannon and Dinarello [36] initially reported that IL-1 levels were increased in plasma from women after ovulation. After ovariectomy, rat peritoneal macrophages had an increase in IL-1 with HRT compared with males and those without replacement. Human male monocytes also demonstrated increased IL-1 after acute estradiol exposure [37]. These studies are problematic in that they involve animal models and male monocytes. Others demonstrated that estrogen had no effect on IL-1 production after stimulation in bone marrow aspirates [38] or spontaneous monocyte release from postmenopausal women receiving conjugated estrogens [39]. Finally, Pacifici and colleagues [40] reported that after surgical menopause, patients had higher levels of IL-1 than those that received HRT. Estrogen-mediated downregulation of IL-1 production appears to occur at the level of transcription. Expression of IL-1 mRNA is reportedly decreased in human monocytes and peritoneal macrophages [41].

In an endotoxin murine model, Zuckerman and coworkers [42] demonstrated that animals with estradiol implants had increased TNF in serum, but not in peritoneal macrophages. However, studies in humans generally support an inhibitory effect of estrogens on TNF production. After 12 months of HRT, Aune and associates [43] reported decreased lipopolysaccharide-stimulated monocyte production of tissue factor, thromboxane B₂, and TNF. Tumor necrosis factor inhibition is also seen in unstimulated monocytes from postmenopausal women on HRT [44]. At the level of transcription, Loy and colleagues [45] demonstrated a dose-related decrease in TNF messenger RNA expression in monocytes from premenopausal women.

Estrogens and Growth Factors
Basic fibroblast growth factor, platelet-derived growth factors, insulin-like growth factor (IGF), and epidermal growth factor are a group of peptides that promote proliferation of endothelial cells, SMCs, and matrix proteins. Host cells express specific receptors that are members of the receptor tyrosine kinase family. On binding, the receptor phosphorylates several cytoplasmic proteins, which subsequently link together, translocate to the nucleus, and activate gene transcription. The earliest nuclear event associated with growth factor action is the induction of the proto-oncogene c-fos. In breast tumor cell lines, estrogen may upregulate c-fos expression and synergistically stimulate proliferation with IGFs [46]. Furthermore, the estrogen receptor itself, without its estrogen ligand, might be crucial to growth factor signal transduction. In a pituitary tumor cell line, in the absence of estrogen and serum, the mitogenic response of IGF-1 was blocked by the antiestrogen, ICI 164,384 [47].

Accumulating evidence supports the coupling of estrogen and peptide growth factor signaling pathways. However, these studies are primarily focused on tumor, bone, and reproductive models. Little information exists concerning estrogens and growth factors in vascular tissue. The only in vivo data involve IGF. Insulin-like growth factor production is possibly unique in that it is regulated in part by the gonadal–pituitary axis. In particular, its synthesis is stimulated in the liver by growth hormone. With ovarian failure, it might be expected that postmenopausal women would have upregulation of both growth hormone and IGF production. Indeed, postmenopausal women on HRT have decreased serum levels of IGF-1 compared with those not receiving replacement therapy [48].

A promising area of investigation is the ability of estrogens to attenuate the mitogenic responses of vascular cells to growth factors. Porcine pulmonary artery and human dermal microvascular endothelial cells stimulated with fibroblast growth factor and vascular endothelial growth factor were inhibited with antiestrogens [17]. Estradiol had no effect on vascular endothelial growth factor stimulation and did not alter antiestrogen inhibition. In bovine aortic endothelial cells, Drummond and colleagues [49] demonstrated that estrogen and progesterone antagonized fibroblast growth factor-stimulated proliferation. The mechanism of such antagonism might involve elaboration of growth factor receptors on the affected cell. Interestingly, Lou and colleagues [50] demonstrated downregulation of IGF-1 receptor messenger RNA in aortic smooth muscle treated with estrogen [50].

	Estrogens, Vascular Smooth Muscle, and Extracellular Matrix

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
Fibrous and advanced plaques of atherosclerosis are predominantly composed of SMCs and ECM, and as such, make an attractive target for atheroprevention. After injury, the contractile SMCs assume a synthetic phenotype and begin to proliferate. These cells become highly responsive to mitogens and subsequently migrate into the intima. In the neointima, SMCs continue to proliferate and secrete growth regulatory and matrix proteins.

Estrogens and Vascular Smooth Muscle
Functional estrogen receptors have been identified in saphenous vein SMC and in human coronary arteries [51]. As such, SMCs may serve as an important target for hormonal influence. Although estrogens clearly inhibit intimal hyperplasia, the hormone’s effects on isolated SMC in vitro have offered conflicting results. Some investigators observed no growth or increased growth [52] with estrogen treatment of rat arterial explants. These studies are difficult to interpret because of the use of estrogen isomers other than 17ß-estradiol and the use of male rats. Initially, estrogen-mediated inhibition of SMC proliferation was only observed with supraphysiologic doses. Recently, animal and human studies have demonstrated that physiologic doses of estrogen may decrease thymidine uptake in SMC, with and without exogenous growth factor supplementation [53]. Estrogens also appear to mediate SMC migration. Suzuki and colleagues [53] demonstrated that physiologic estradiol could attenuate human female aortic SMC migration stimulated with platelet-derived growth factor-BB and epidermal growth factor. Similarly, estrogen decreased migration of rat SMC stimulated by platelet-derived growth factor, IGF, and fibronectin [54].

Estrogens and Extracellular Matrix
After migrating to the intima, SMCs persist in the synthetic, secretory phenotype where they produce collagen, elastin, and proteoglycans. Indeed, the ECM can contribute up to 70% by volume of the mature intimal lesion. After ovariectomy, cholesterol-fed rats receiving HRT demonstrated less aortic collagen accumulation and hydroxyproline activity [55]. These observations may be directly linked to estrogen’s effect on SMC biosynthesis of collagen. In cultured bovine aortic SMCs, estrogen exposure reduced collagen, procollagen I, and procollagen III production [56].

	Summary

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 
Unlike many drugs, exogenous estrogens have been used for decades without an understanding of their mechanism of action. Clearly, atheroprotection is not adequately explained by favorable changes in lipid metabolism. Within the response to injury paradigm of atherogenesis, accumulating evidence suggests that estrogens may intervene at several points of vascular remodeling. At the level of the endothelium, estrogens augment reendothelialization, attenuate endothelial cell apoptosis, and promote NO and prostacyclin production, thus preserving vasomotor function. In flow-dependent studies, estrogens decrease endothelial and leukocyte adhesion molecule formation, thus decreasing the ability of inflammatory mediators to migrate into an injured vessel. Once in the vessel, it appears that estrogens can decrease the expression of the mitogenic cytokines, TNF and IL-1. Although studies are limited, estrogens may not only decrease the production of proliferative peptides, but may also attenuate the vascular SMC mitogenic response to growth factors. In addition to inhibiting the proliferation and migration of vascular SMCs into the neointima, estrogens can also directly modify the developing plaque by decreasing the production of ECM proteins. The importance of estrogens in mediating cardiovascular protection in premenopausal women and postmenopausal women on HRT is strongly supported epidemiologically. As such, estrogens provide a useful clinical and experimental model for delineating key events in atherogenesis. Focused mechanistic studies interrogating estrogen-mediated atheroprotection may provide insight to targeted therapeutic strategies that may be accessible to all cardiovascular surgery patients.

	References

Top Abstract Introduction Estrogens and Cardiovascular... Estrogens and Endothelium Estrogens and Leukocyte Adhesion Estrogens, Cytokines, and Growth... Estrogens, Vascular Smooth... Summary References

 

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