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EDITORIAL FOCUS
Departments of 1Surgery and 2Physiology and Bioengineering, Mayo Clinic College of Medicine, Rochester, Minnesota
CARDIOVASCULAR DISEASE is a leading cause of death, the rate of which is greater in men compared with age-matched premenopausal women (1). However, the long-standing hypothesis that estrogen may contribute to this sex-based difference in disease presentation by providing "vascular protection" has recently come under fire. The controversy that estrogen protects against cardiovascular disease arose because results of randomized clinical trials conducted in postmenopausal women using conjugated equine estrogen in combination with medroxyprogesterone acetate for secondary (Heart and Estrogen/progestin Replacement Study, Ref. 14) and primary (Women’s Health Initiative, Ref. 27) prevention failed to show reductions in myocardial infarction and stroke as was predicted based on observational studies of newly menopausal women using estrogen products to relieve symptoms of menopause (2, 4, 6, 11, 18). Explanations of why these differences exist between epidemiologic studies and randomized trials need to be explored mechanistically, including the timing for initiation of estrogen intervention and the type and mode of hormonal treatment used (12), as the majority of evidence provided from the basic science literature indicates that estrogen treatments initiated shortly after ovariectomy of experimental animals reduces vascular response to injury, i.e., provides vascular protection (5). Such protection is likely to occur in males as well as females, as in humans genetic variance in one estrogen receptor (ER), ER-
, is associated with increased atherosclerosis and adverse outcomes in men (23, 24).
Receptors for estrogen have been identified in all components of the vascular wall (endothelium, smooth muscle, adventitial cells). In endothelial cells, several mechanisms are identified by which estrogen, through ligation of its receptor or independent of its receptor, modulate gene transcription, mRNA stability, translation, and posttranslational protein function (for review, see Ref. 21). However, less is known about estrogenic regulation in vascular smooth muscle cells. The paper by Kappert et al. in this issue (16a) adds important information to fill this gap in our knowledge by providing evidence that estrogen and its metabolite methoxyestradiol reduce PDGF receptor (PDGFR)-activated migration and proliferation of cultured aortic smooth muscle cells derived from male rats by inhibiting the downstream signaling activity of rac-1 (Fig. 1). This inhibition is signaled through ERs without affecting PDGFR expression/phosphorylation or consecutive binding of receptor-associated Src homology region 2-containing signaling molecules such as Src homology region 2-containing phosphatase-2, PLC-
, phosphatidylinositol 3-kinase, RasGAP, and p85. Because proliferation and migration of vascular smooth muscle cells are two processes needed for development of myointimal thickening after vascular injury, identification of cellular processes that limit these processes such as inhibition of Rac1GTPase provides information about how estrogen could limit vascular disease and potential target molecules for new therapeutic interventions.
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-estradiol) through ER- (10). In mouse aortic smooth muscle cells, estrogen reduced the growth by downregulation of PDGFR and limited activation of ERK (9). Growth factors activate ER--mediated gene expression in vascular cells through the AF-1 domain of ER- but not by activation of the MAPK pathway (17). Therefore, the results of the Kappert study (16a) identify an important, yet perhaps redundant, pathway by which estrogen modulates PDGF-activated cell processes. rac-1 is a small (21 kDa) member of the Rho family of proteins/GTPase. Estrogen downregulates rac-1 mRNA, protein, and activity in cells derived from female animals including that required for angiotensin II-induced NADPH oxidase activity and reactive oxygen production, ovariectomy-induced increases in expression in smooth muscle of spontaneously hypertensive rats, and expression in mononuclear cells derived from women with ovarian hyperstimulation (19). Because estrogen treatment affected the rac-1 pathway in cells derived from male animals, the study provides important insights into how estrogen affects vascular function in males as well as females (25).
Another exciting observation from the study of Kappert et al. (16a) is that the estrogen metabolite methoxyestradiol was also efficacious in inhibiting rac-1. This observation confirms that metabolites of estrogen also have protective activities and suggests that metabolism of 17-estradiol within vascular tissue activates molecules that bind ERs, perhaps modulating the threshold, duration, and amplitude of the estrogen signal (8, 20, 22). These data also pose the question as to how genetic variation in enzymes required for estrogen metabolism affects individual response to estrogen or susceptibility for cardiovascular disease, that is, polygenomic (receptors, enzymes) variation in estrogenic responses.
When considering the integrated physiological actions of estrogen, it is important to keep in mind that in intact animals, including humans, estrogen could affect the production of PDGF as well as its receptor downstream signaling mechanisms. For example, with ovariectomy content of PDGF in platelets increases, which sustains proliferation of cultured smooth muscle cells in female pigs (3, 16). Therefore, with an estrogen-replete condition, both decrease in production of PDGF and inhibition of PDGFR-ligated signaling cascades would act to reduce and/or limit smooth muscle migration and proliferation in response to injury.
Several key questions arise from the study of Kappert et al. (16a). Importantly, it is not clear that the receptor-ligated effects of estrogen are mediated by ER-. Although no changes in expression of ER- were reported under the conditions of their experiments, identification of ER- and its regulation remain to be determined, as ER- may be more prominent in smooth muscle of males than females (13). In addition, are the effects of estrogen metabolites mediated through the same receptors? Another interesting issue is whether and how caveolin participates in regulation of ER, PDGFR, and rac-1 (7). Caveolin is a 21- to 24-kDa integral membrane protein that modulates residential signaling molecules in membrane invaginations called caveolae. Estrogen treatment increases caveolin-1 mRNA and protein expression in cultured bovine endothelial cells and rat vascular smooth muscle cells (15, 26). However, modulation of caveolin-1 mRNA and protein by PDGF and subsequent activation of rac-1 expression and activity have yet to be examined.
In summary, the paper by Kappert and colleagues (16a) provides additional mechanistic support to the hypothesis that estrogen provides vascular protection. Importantly, the study identifies the contribution of rac-1, the participation of estrogen metabolites, and the suggestion that estrogen affects comparable intracellular pathways in cells from males and females.
FOOTNOTES
Address for reprint requests and other correspondence: V. M. Miller, Dept. of Surgery, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 (e-mail: miller.virginia{at}mayo.edu)
REFERENCES
and . Prevalence of estrogen receptor mRNA in human vascular smooth muscle and transcriptional effects. Circulation 101: 1792–1798, 2000.-estradiol on caveolin-1 mRNA and protein in bovine aortic endothelial cells. Am J Physiol Heart Circ Physiol 281: H1327–H1333, 2001.-estradiol, conjugated equine estrogen, and raloxifene on mRNA expression, aggregation, and secretion in platelets. Am J Physiol Heart Circ Physiol 288: H2355–H2362, 2005.-Estradiol attenuates PDGF signaling in vascular smooth muscle cells at the postreceptor level. Am J Physiol Heart Circ Physiol 290: H538–H546, 2006. gene variation and cardiovascular disease. JAMA 290: 2263–2270, 2003.This article has been cited by other articles:
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  M. Pretorius, G. P. van Guilder, R. J. Guzman, J. M. Luther, and N. J. Brown 17{beta}-Estradiol Increases Basal but Not Bradykinin-Stimulated Release of Active t-PA in Young Postmenopausal Women Hypertension, April 1, 2008; 51(4): 1190 - 1196. [Abstract] [Full Text] [PDF]
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