Commentary on Liu et al
Effect of Estrogen and AT1 Receptor Blocker on Neointima Formation
Epidemiological studies demonstrate sexual dimorphism with respect to arterial blood pressure, incidence of vascular disease, and the rate of progression of renal disease. In this regard, in men age <60 years, arterial blood pressure is higher compared with that of age-matched women, and the incidence of coronary artery disease is 50% less in premenopausal women compared with age-matched men. Decline of kidney function in patients with chronic renal disease is slowed in premenopausal women compared with age-matched men.
After the loss of ovarian function, sexual dimorphisms vis-à-vis hypertension, vascular disease, and rate of progression of kidney disease are no longer present. Arterial blood pressure increases in postmenopausal women, and the incidence of vascular disease and the rate of progression of renal disease equalizes between men and women.
The association of loss of ovarian function and disappearance of sexual dimorphism with respect to hypertension and vascular and renal disease suggests that 17β-estradiol, the major estrogen produced by the human ovary, may importantly participate in the relative protection afforded to premenopausal women. The conclusion that 17β-estradiol protects against hypertension, vascular damage, and progression of renal disease is corroborated by animal studies demonstrating antihypertensive, vasculoprotective, and renoprotective effects of 17β-estradiol.
Like 17β-estradiol, inhibitors of the renin-angiotensin system, such as ACE inhibitors or angiotensin receptor blockers (ARBs), also reduce blood pressure, protect blood vessels against vascular injury, and have renoprotective effects. Whether these beneficial effects of inhibitors of the renin-angiotensin system are nonadditive, additive, or synergistic with 17β-estradiol is a critically important question that was addressed by Liu and coworkers1 in this issue of Hypertension.
Liu et al1 induced vascular injury in mice by placing a cuff around the femoral artery, and 14 days later, they assessed the response to vascular injury morphometrically and histochemically. Drug treatments were begun 1 day before (17β-estradiol) or at the time of (olmesartan, an ARB) cuff placement.
As reported by others,2 the vascular injury response in females was less than in males, and ovariectomy abolished and estradiol-replacement therapy restored this sexual dimorphism. Importantly, Liu et al also observed a sexual dimorphism with regard to the vasoprotective effects afforded by olmesartan. Olmesartan was more effective in reducing the vascular response to injury in female compared with male mice, and ovariectomy abolished the enhanced effectiveness of olmesartan in females. Moreover, in ovariectomized female mice, combined low doses of 17β-estradiol and olmesartan—which were per se ineffective in reducing the response to vascular injury—markedly attenuated neointimal hyperplasia and vascular smooth muscle cell (VSMC) proliferation in the intima and media. These are novel findings with significant clinical implications.
Multiple and interacting signal transduction pathways mediate the vascular response to injury.3 In particular, activation of extracellular signal-regulated kinases (ERKs) and signal transducers and activators of transcription (STATs) participate in the upregulation of VSMC proliferation induced by vascular injury. To investigate whether ARBs and 17β-estradiol interact at the level of these key signal transduction pathways, Liu et al1 also examined by Western blotting the steady state levels of phosphorylated (activated) ERK-1, ERK-2, STAT1, and STAT3 in normal and injured femoral arteries. In both male and female mice, vascular injury caused a multifold increase in vascular levels of activated ERKs and STATs; however, these responses were attenuated in female mice, and ovariectomy abolished and estradiol-replacement therapy restored this sexual dimorphism. As with the morphological responses, olmesartan was more effective in reducing injury-induced activation of ERKs and STATs in female compared with male mice. Ovariectomy abolished and estradiol-replacement therapy restored the enhanced ability of olmesartan to inhibit ERK and STAT activation in female mice. Moreover, in ovariectomized female mice, combined low doses of 17β-estradiol and olmesartan—which were per se ineffective in blocking injury-induced activation of ERKs and STATs—markedly attenuated injury-induced activation of ERKs and STATs. These findings are completely congruent with the morphometric and histochemical results.
A strong inference from the results reported by Liu et al1 is that 17β-estradiol and ARBs synergistically attenuate the vascular injury response. This benchmark study has at least 3 major implications for the prevention and treatment of vascular diseases—such as atherosclerosis, bypass graft failure, and restenosis following angioplasty—in patients. One implication is that ARBs may be more effective with respect to the prevention and treatment of vascular diseases in patients with high levels of endogenous 17β-estradiol, such as premenopausal women, versus patients with low levels of endogenous 17β-estradiol, such as postmenopausal women and men. A second inference is that in patients with low endogenous levels of 17β-estradiol, higher doses of ARBs may be required to achieve maximum benefits with regard to protecting blood vessels. A third implication is that in postmenopausal women, the benefits of ARBs may be enhanced by the coadministration of 17β-estradiol (but not necessarily other estrogenic preparations).
The study by Liu et al1 raises a number of pressing questions. First, is there also a synergy between 17β-estradiol and ACE inhibitors with regard to vasculoprotection? Presumably, the same benefits obtained by combining 17β-estradiol with an ARB would be gained by coadministering 17β-estradiol with an ACE inhibitor because ARBs and ACE inhibitors share the common denominator of inhibition of the renin-angiotensin system. Nonetheless, this extrapolation needs to be confirmed experimentally.
Second, is there also a synergy between 17β-estradiol and inhibitors of the renin-angiotensin system with respect to lowering blood pressure in hypertensive states and attenuating the rate of decline of renal function in chronic renal failure? There is evidence that ERKs are involved in the pathogenesis of hypertension and progression of renal disease, and therefore it is conceivable that 17β-estradiol would potentiate the antihypertensive and renoprotective actions of ARBs and ACE inhibitors.
Third, does 17β-estradiol potentiate the actions of ARBs via an estrogen receptor (ER)–mediated mechanism? Whether 17β-estradiol attenuates the vascular injury response via an ER-dependent mechanism remains an open question. In one study, the ability of 17β-estradiol to attenuate the vascular injury response was the same in wild-type versus ERαChapel Hill knockout mice,4 and in another study, the vasculoprotecive effects of 17β-estradiol were similar in wild-type versus ERβChapel Hill knockout mice.5 In yet another study, 17β-estradiol still inhibited VSMC proliferation in ERα/ βChapel Hill double-knockout mice.6 However, ERαChapel Hill knockout mice may express a splice variant with residual activity. In a more recent study, Pare et al7 observed that in ERαStrasbourg knockout mice, 17β-estradiol had no effect on the vascular injury response. Unfortunately, the vascular injury response in untreated ERαStrasbourg knockout mice was markedly suppressed. In fact, in the Strasbourg mouse, knocking out ERα was approximately as effective as administering 17β-estradiol to wild-type with respect to protecting against vascular injury. Therefore, the lack of effect of 17β-estradiol in ERαStrasbourg knockout mice might have been caused by the meager vascular injury response in untreated ERαStrasbourg knockout mice.
It is critical not to confuse the terms 17β-estradiol, conjugated equine estrogen, and estrogen. The term 17β-estradiol refers to a specific steroid with a defined molecular structure. Conjugated equine estrogen is a mixture of steroids extracted from pregnant equine urine and is of uncertain composition, but its primary active ingredients are sodium estrone sulfate, sodium equilin sulfate, and sodium 17α-dihydroequilenin. The term estrogen refers to any preparation that activates estrogen receptors. Although both 17β-estradiol and conjugated equine estrogen are estrogens, 17β-estradiol is not equal to conjugated equine estrogen. In this regard, conjugated equine estrogen contains very little 17β-estradiol and therefore would not mimic the non–ER-mediated effects of 17β-estradiol.
Extensive animal studies demonstrate that 17β-estradiol protects the heart, blood vessels and kidneys. Unfortunately, all of the randomized, placebo-controlled, prospective, long-term mega-trials in women, specifically the Heart and Estrogen/Progestin Replacement Study (HERS),8 the HERS II study,9 and the Women’s Health Initiative (WHI) Study,10 were conducted with conjugated equine estrogen, not 17β-estradiol. These studies were disappointing in that conjugated equine estrogen did not afford protection against cardiovascular disease in either a primary or secondary prevention setting. In contrast, in the Estrogen Prevention of Atherosclerosis Trial,11 a small (n=222 postmenopausal women), short-term (2 years of follow-up) primary prevention study, 17β-estradiol significantly reduced the rate of progression of atherosclerosis. In the final analysis, perhaps “nature knows best,” and we should institute hormone replacement therapy with the hormone that needs to be replaced, ie, 17β-estradiol, rather than with an extract of horse urine. What a radical idea!
In summary, the findings reported by Liu and coworkers1 introduce a new concept for the treatment and prevention of vascular disease, ie, the combination of 17β-estradiol with inhibitors of the renin-angiotensin system. Much work remains to be done to elucidate the mechanism of and to ascertain the full clinical significance of this important interaction. In view of the negative findings by the HERS, HERS II, and the WHI studies, it may become increasingly difficult to fund research on the cardioprotective effects of 17β-estradiol. This researcher hopes that the American public and the National Institutes of Health will remain patient while we strive to understand these complex issues.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N, for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA. 2002; 288: 49–57.