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Angiotensin II type 1 receptors and oestrogen status: interaction or dissociation?

Zhuo, Jia L.

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Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan, USA.

Correspondence and requests for reprints to Jia L. Zhuo, Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI 48202, USA. Tel: +1313 916 4958; fax: +1313 916 1479; e-mail: jzhuo1@hfhs.org

The renin–angiotensin system (RAS) and oestrogen status are two of the most common risk factors implicated in the pathogenesis of hypertension, atherosclerosis and ischaemic heart disease [1–4]. Indeed, development and progression of hypertension, atherosclerosis, and ischaemic heart disease have been attributed to over-activation of the RAS [as reflected by increased expression and/or production of its major components, including renin, angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II type 1 (AT1) receptors], as well as to deficiency of oestrogen after menopause [1–4]. Angiotensin II acts on AT1 receptors to induce vasoconstriction, stimulate cell growth and increase NADH/NADPH oxidase-derived superoxide anion in cardiovascular cells [1,5,6]. These actions of angiotensin II are pro-atherosclerotic and may be the leading causes of the endothelial dysfunction seen in hypertension, atherosclerosis and ischaemic heart disease [1,5,6]. By contrast, oestrogen was generally believed to be cardioprotective [3,7] until the controversial findings of the prospective Heart Oestrogen/Progestin Replacement Study (HERS) [8]. There is also substantial evidence from human and animal studies that oestrogen may provide beneficial cardiovascular effects by modulating the RAS. Oestrogen has been shown to inhibit circulating renin and ACE, decrease circulating angiotensin II levels [9–12] and downregulate AT1 receptor expression in vascular smooth muscle cells, adrenal cortex and hypothalamus [13–16]. Conversely, oestrogen deficiency as a result of menopause or ovariectomy has the opposite effects on the RAS [13,17,18]. Hence, it is not surprising that the vasoconstrictor response to angiotensin II is attenuated by oestrogen [19,20], whereas oestrogen deficiency enhances the vasoconstrictor response to angiotensin II by upregulating AT1 receptors [17]. For these reasons, oestrogen replacement therapy and blockade of the RAS with ACE inhibitors or AT1 receptor antagonists may be beneficial in restoring vascular endothelial dysfunction, lowering blood pressure and preventing the development of cardiovascular disease [1,2,6,7, 17,20].

Against this background, in this issue of the journal, Riveiro et al. report on their studies of whether oestrogen modulates the effects of AT1 receptor blockade on vascular endothelial function in ovariectomized and sham-ovariectomized spontaneously hypertensive rat (SHR) [21]. Both groups were treated with the AT1 receptor antagonist irbesartan (50 mg/kg per day) for 30 weeks, and the vascular reactivity of aortic rings was compared at the end of the treatment period. In contrast to previous reports [17,19,20], they showed that endothelium-dependent vascular reactivity, as represented by responses to the nitric oxide synthase inhibitor l-NAME, phenylephrine and acetylcholine, was the same in irbesartan-treated ovariectomized and sham-ovariectomized SHR. The authors concluded that, in SHR, oestrogen does not play a role in the improvement of the vascular endothelial dysfunction observed after long-term AT1 receptor blockade. Although Riveiro et al. did not deal with the complex mechanisms underlying the lack of oestrogen modulation in the improved endothelial function produced by blocking the AT1 receptor with irbesartan, their findings clearly show that lack of oestrogen does not alter both endothelium-dependent and -independent relaxation in SHR after long-term treatment with irbesartan, regardless of oestrogen status [21]. The results are generally in accordance with the HERS clinical trial, which found that hormone replacement therapy has no beneficial cardioprotective effects [8]. However, the conclusion reached by Riveiro et al. that oestrogen has no beneficial cardiovascular effects should be viewed with caution, because ovariectomy removes the influences of all sexual steroids, and not just oestrogen. As the effects of oestrogen replacement were not studied in separate groups of ovariectomized animals, it is difficult to draw the conclusion that other sexual hormones produced by the ovaries do not modulate the vascular responses to AT1 receptor blockade. Moreover, the data are inconsistent with previous observations that oestrogen modulates the expression and/or production of major components of the RAS [9–15], as well as those published recently by Wassmann et al. who examined the role of oestrogen deficiency in endothelial dysfunction in ovariectomized SHR and found that it led to an enhanced vasoconstrictor response to angiotensin II associated with upregulation of vascular AT1 receptors and increased superoxide production in the vascular wall [17]. Five weeks of treatment with the AT1 receptor blocker irbesartan or oestrogen replacement with 17β-oestradiol similarly prevented endothelial dysfunction and normalized vascular superoxide levels in ovariectomized SHR [17]. These data suggest that angiotensin II and oestrogen may interact physiologically to maintain vascular endothelial function, and an imbalance of these interactions may play an important role in endothelial dysfunction during hypertension and cardiovascular disease.

The study by Riveiro et al. is not the only one to report a negative effect of oestrogen on vascular reactivity to angiotensin II or AT1 receptor blockade. For example, cardiovascular haemodynamic responses to angiotensin II are similar in female rats whether or not they undergo ovariectomy or oestrogen replacement [22]. In premenopausal women, renal and peripheral haemodynamic responses to the AT1 receptor blocker losartan are also similar in the high and low oestrogen phases of the menstrual cycle [23]. Thus, whether or not oestrogen is cardioprotective through interactions with angiotensin II remains controversial, and the causes underlying these conflicting results are more complex than previously thought. They may reflect differences in the animal models used (normotensive versus hypertensive), species (rats or mice versus humans), vessels studied (aorta versus other peripheral vessels), in-vitro versus ex-vivo conditions, and the length of ovariectomy and drug therapy (weeks versus months). One unique characteristic of the study by Riveiro et al. is that their experiments were performed 30 weeks after ovariectomy and/or irbesartan treatment, which may be relevant to clinical studies such as HERS [8]. However, because the experiments were only performed on vessels harvested from animals 30 weeks after ovariectomy or irbesartan treatment, the data might overlook differences in the expression of vascular AT1 receptors and/or vascular reactivity to AT1 receptor blockade, which may be present during the early stages of ovariectomy in SHR [17–19]. Long-term administration of AT1 receptor antagonists is also associated with increased circulating levels of angiotensin II [24,25], which may act on unopposed angiotensin II type 2 receptors (AT2) [26]. AT2 receptor activation via interactions with kinins and nitric oxide [26] may obscure differences in vascular reactivity to long-term irbesartan administration regardless of oestrogen status. Thus, the observation that oestrogen status fails to alter endothelium-dependent responses to angiotensin II or long-term AT1 receptor blockade should encourage, rather than deter, further exploration of interactions between oestrogen and angiotensin II and the mechanisms involved in the cardiovascular effects of oestrogen.

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