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Am J Physiol Heart Circ Physiol 292: H2566-H2569, 2007. First published March 9, 2007; doi:10.1152/ajpheart.00193.2007
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EDITORIAL FOCUS

Estrogen-TNF interactions and vascular inflammation

Nicholas R. Ferreri

Department of Pharmacology, New York Medical College, Valhalla, New York

CARDIOVASCULAR DISEASE (CVD), especially coronary heart disease (CHD), is by far the leading cause of death in women (29, 40). As the prevalence of these diseases increases after menopause, much effort has been devoted to determining whether endogenous estrogen confers a protective effect against CVD and whether hormonal replacement therapy after menopause might be of benefit. However, a simple paradigm of estrogen protection in postmenopausal women may not be tenable from the results from recent clinical trials that evaluated the effects of hormonal replacement therapy on CVD in women; namely, several studies concluded that hormonal therapy does not appear to be efficacious (2, 6, 16, 25, 29, 59). Moreover, the Women's Health Initiative (WHI) showed that replacement therapy with conjugated equine estrogens (CEEs) and medroxyprogesterone acetate actually increased the incidence of coronary events (20, 44). Although the conclusions of the WHI may have been influenced by several factors, including concurrent administration of medroxyprogesterone along with CEEs, or the source of estrogen used, the "estrogen only" arm of the study also has been terminated (35, 38, 42). However, a regimen of CEEs alone reduced the number of cardiovascular events in women between the ages of 50 and 59 yr, an effect that may be negated with aging (20). Thus there is a need to reconcile the results of clinical trials that fail to demonstrate a cardioprotective effect of estrogen versus prodigious amounts of data showing that estrogen has beneficial effects on the cardiovascular system (17).

Alterations in vascular function, including a reduction in responses to shear stress and reduced bioavailability of nitric oxide, as well as increased cardiovascular risk associated with aging appear related to the onset of menopause (29, 52, 55, 57). Accordingly, estrogen deficiency may be associated with some of the attendant cardiovascular risks in women after menopause, and novel mechanisms by which decreased levels of sex hormones contribute to the increased risks need to be identified. As the mechanisms by which estrogen confers protection against arterial vascular disease while increasing risk of venous thrombosis are not clear, a better understanding of the interactions of estrogen with diverse sets of molecules and their effects on the peripheral vasculature also may elucidate ways to identify the subset of women in whom postmenopausal treatment with estrogen is a risk factor for venous thromboembolism (26). Humoral factors such as cytokines as well as other cellular factors that affect blood vessels and circulating elements are likely to cooperate in a manner that determines, in part, the incidence of venous thromboembolic disease, and the link between inflammation and CVD adds to the complexity of potential interactions and complicating factors (13, 28). Activation of two distinct receptors for estrogen (ER; {alpha} and beta) contributes importantly to the effects of this hormone. Both receptors have been linked to mechanisms relevant to inflammation, platelet activation, and regulation of the renin angiotensin system (RAS) that influence the effects of estrogen on cardiovascular physiology and pathophysiology. In this issue of the American Journal of Physiology-Heart Circualtory Physiology, Xing et al. (61) demonstrate that estrogen attenuates tumor necrosis factor-{alpha} (TNF)-mediated production of the chemokine cytokine-induced neutrophil chemoattractant (CINC)-2beta in vascular smooth muscle cells (VSMC) via an estrogen (E2) beta-receptor-dependent mechanism.

TNF is a pleiotropic cytokine that participates in innate immunity and adaptive immune responses, and the presence of TNF receptors on virtually all cells accounts for the diverse effects of TNF, including the ability to activate an impressive variety of genes (56). Although the capacity to produce TNF was first described for macrophages and T lymphocytes, nonhematopoietic cells, including VSMC cells, also produce this cytokine. TNF is expressed in VSMC after balloon injury, restenotic lesions, intimal VSMC, as well as plaques of atherosclerotic arteries, and models of transplantation-associated atherosclerosis (5, 8, 22, 37, 45, 54, 56, 58). TNF induces rapid depolymerization of F-actin fibers, the disappearance of vinculin from focal adhesions in VSMC; migration of cultured rat aortic VSMC was linked to VSMC proliferation in vivo and in vitro (14, 22, 53, 54, 63). Given the emerging role of TNF as a regulator of cardiovascular physiology and pathophysiology, it is significant Xing et al. demonstrate that estrogen antagonizes proinflammatory effects of TNF (61). VSMC express both types of TNF receptors (p55, TNFR1, and p75, TNFR2), and the ability of this cytokine to upregulate expression of adhesion molecules and chemokines that facilitate migration of leukocytes into sites of inflammation has been associated with restenosis (9, 14). Experiments employing specific antibodies against TNFR1 and TNFR2, or TNFR-deficient mice, suggest that most inflammatory responses are mediated via activation of TNFR1 (11, 34, 46, 47). For instance, TNF is a positive regulator of neointimal hyperplasia and arteriogenesis in response to low shear stress, the latter being related to a selective effect via activation of TNFR1 (12, 19, 41). Moreover, TNFR1-deficient mice exhibited a twofold reduction in intimal hyperplasia after balloon injury of the murine carotid artery compared with TNFR2 knockout mice and wild-type mice (64). Induction of chemokines by TNF also has been shown to be TNFR1 dependent (1, 48). Collectively, these studies indicate that VSMC can both produce and respond to TNF, events that may contribute importantly to the pathogenesis of CVD and be subject to regulation by estrogen.

Although TNF production is tightly regulated, serum levels of this cytokine have been reported to be elevated in postmenopausal women and ovariectomized rats (3, 23, 50). These data are consistent with in vitro data showing that estrogen inhibits TNF gene transcription via E2beta receptors (51). The study by Xing et al. (61) illustrates an additional mechanism by which estrogen may confer protective effects against inflammation in the cardiovascular system, that is, inhibition of TNF-mediated chemokine production by VSMC. Previously, these authors showed that estrogen inhibited neutrophil infiltration into injured arteries by inhibiting production of CINC-2beta, a CXC chemokine family member (27). The present study demonstrates in VSMC that 17beta-estradiol (E2) attenuates TNF-mediated increases in the expression of adhesion molecules and chemoattractants. This effect occurred via a selective effect of estrogen on E2beta receptors and prevented expression of P-selectin, intercellular adhesion molecule-1, vascular adhesion molecule-1, MCP-1, as well as CINC-2beta. Decreased expression of these molecules was associated with a reduction in mRNA accumulation, which may reflect an inhibitory effect of estrogen on gene transcription and/or mRNA stability. Moreover, inhibition of these molecules was associated with a decrease in TNF-mediated chemotaxis of neutrophils. The synthesis of proinflammatory molecules by VSMC is highlighted as part of a TNF-dependent mechanism that contributes to the infiltration of neutrophils into the injured vasculature and implicates VSMC as an important source of CINC-2beta and, therefore, as a cell type that contributes to the profile of mediators that govern the inflammatory response to TNF.

The implications of elevated TNF levels in the context of reduced levels of sex hormones also relate to impaired function of the vascular endothelium associated with a decrease in nitric oxide availability, a mechanism that may be coupled to increased release of superoxide as well as a decrease in endothelial nitric oxide synthase expression by endothelial cells (3, 30, 62). Thus the ability of estrogen to inhibit expression of adhesion molecules is not limited to VSMC and has been observed in cultured human endothelial cells as well as animal models of atherosclerosis (7, 15). Clearly, the in vivo effects of estrogens that contribute to a protective effect against CVD are complex and mediated via interactions of several important mechanisms that affect diverse regulators of vascular function, blood pressure homeostasis, and other determinants of overall cardiovascular health. For instance, estrogen deficiency has been associated with activation of the RAS, increased salt sensitivity, hypertension, an increase in oxidative stress, and endothelial cell dysfunction in response to endothelin and ANG II (10, 18, 21, 39, 40). Moreover, estrogen attenuated the vasoconstrictor response to phenylephrine as did neutralization of TNF bioactivity by treatment with etanercept, suggesting that vascular hypersensitivity may be mediated by TNF and the RAS when estrogen levels are low as in aging female rats and postmenopausal women (4). Thus the intricacies of these and other relationships that may be subject to age-dependent effectiveness in postmenopausal women could complicate the interpretation of data that question the utility of hormonal replacement therapy as a means to achieve protection against CVD (44). However, it is important to note that secondary factors and/or age-related changes that are independent of estrogen deficiency also may predispose subsets of women to CVD (39).

The study by Xing et al. (61) supports the concept that VSMC contribute to an inflammatory response by releasing several molecules, after challenge with TNF, that are essential to the process. Estrogen attenuates VSMC expression of adhesion molecules and chemoattractants, including a member of the CINC family of chemokines CINC-2beta, and activation of ERbeta in VSMC has protective effects relevant to vascular inflammation. Because ER{alpha} receptors also have been linked to protective effects on vascular injury, understanding apparent differential effects of estrogen receptors observed in a cell type-dependent manner may provide additional information regarding the mechanisms by which estrogen affects cardiovascular function (33). However, Xing et al. (61) acknowledge that the estrogen receptor agonists used in their study are not pure ER{alpha} or ERbeta agonists, and additional strategies will be required to confirm their results. It will be important to determine the molecular mechanisms by which activation of E2beta receptors in VSMC interrupts CINC-2beta mRNA accumulation and to determine whether estrogen exerts nongenomic effects that alter signaling via TNF receptors; the role played by TNFR1 and TNFR2 also is of interest. For instance, estrogen inhibits platelet-derived growth factor (PDGF)-induced migration and proliferation of VSMC by decreasing rac-1 activity, an effect independent of PDGF receptor phosphorylation or expression (24). ANG II may contribute to the pathogenesis of CVD associated with altered vascular function in postmenopausal women and experimental models of estrogen deficiency as upregulation of angiotensin-converting enzyme and ANG II type I receptor (AT1) receptors was observed in both instances (4, 31, 36). Conversely, estrogen decreases expression of AT1 receptors in several tissues (32, 43, 60). Thus it is intriguing to speculate that the ability of estrogen to downregulate expression of AT1 receptors could offer another potential interaction between this hormone and TNF since production of this cytokine in the kidney is AT1 receptor dependent (49). Moreover, since estrogen reduces expression of AT1 receptors, the possibility of a similar effect on expression of TNF receptors should be addressed. Counterregulatory pathways that limit damage caused by cytokines, induced to levels that are no longer beneficial and become part of the pathophysiology associated with CVD, may be critical to maintaining the effectiveness of homeostatic mechanisms. The demonstration by Xing et al. (61) that estrogen can act as an antagonist of TNF-mediated proinflammatory pathways via inhibition of CINC-2beta production and subsequent neutrophil migration is especially noteworthy in this regard.

FOOTNOTES


Address for reprint requests and other correspondence: N. R. Ferreri, Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595 (e-mail: nick_ferreri{at}nymc.edu)

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