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Am J Physiol Heart Circ Physiol 294: H156-H163, 2008. First published November 2, 2007; doi:10.1152/ajpheart.01137.2007
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The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic

H. Girouard,1 A. Lessard,1 C. Capone,1 T. A. Milner,1,2 and C. Iadecola1

1Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College; and 2Harold and Margaret Milliken Hatch Laboratory of Neuroendociniology, The Rockefeller University, New York, New York

Submitted 2 October 2007 ; accepted in final form 1 November 2007


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Women are less susceptible to the cerebrovascular complications of hypertension, such as a stroke and vascular dementia. The mechanism of such protection may be related to a reduced vulnerability of women to the cerebrovascular actions of hypertension. To test this hypothesis, we used a model of hypertension based on infusion of angiotensin II (ANG II), an octapeptide that plays a key role in hypertension and produces cerebrovascular dysregulation. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6J male and female mice equipped with a cranial window. ANG II administration (0.25 µg·kg–1·min–1 iv x 30–45 min) elevated arterial pressure equally in both sexes but attenuated the CBF increase induced by whisker stimulation or by the endothelium-dependent vasodilator acetylcholine (ACh) in male but not in female mice. The administration of ANG II for 7 days (2.74 mg·kg–1·day–1), using osmotic minipumps, also attenuated these cerebrovascular responses in male, but not female, mice. The reduced susceptibility to the effect of ANG II in female mice was abolished by ovariectomy and reinstated by estrogen administration to ovariectomized mice. Administration of estrogen to male mice abolished the ANG II-induced attenuation of CBF responses. We conclude that female mice are less susceptible to the cerebrovascular dysregulation induced by ANG II, an effect related to estrogen. Such protection from the deleterious cerebrovascular effects of hypertension may play a role in the reduced vulnerability to the cerebrovascular complications of hypertension observed in women.

hypertension; functional hyperemia; endothelium-dependent relaxation; estrogen

WOMEN ARE RELATIVELY PROTECTED from cardiovascular and cerebrovascular diseases (see Ref. 15 for a review). Thus the age-adjusted incidence of ischemic stroke is less in women than in men, even if hypertension is present (40). The biological bases of the reduced susceptibility to cerebrovascular diseases in women are not completely understood, but there is evidence that reproductive hormones, estrogen in particular, are involved (18, 25). Estrogen produces vasodilation, has anti-inflammatory properties, reduces lipids, and scavenges reactive oxygen species (ROS) (6, 18, 25). These beneficial effects of estrogen are thought to promote vascular health by reducing atherosclerosis and counteracting the deleterious effects of hypertension (25).

Hypertension has powerful effects on the cerebral circulation and is the major risk factor for stroke and vascular cognitive impairment (37, 41). Hypertension alters the structure of cerebral blood vessels (2, 34) and disrupts vital control mechanisms that regulate cerebral blood flow (CBF), such as autoregulation, endothelium-dependent vasodilation, and the increased CBF evoked by neural activity (functional hyperemia) (10). These structural and functional cerebrovascular changes compromise the cerebral blood supply and increase the susceptibility of the brain to ischemic injury (17, 35). The octapeptide angiotensin II (ANG II), a major factor in the development of hypertension, is thought to play a key role in these cerebrovascular alterations (10, 33).

When we consider the prominent role of hypertension in determining stroke risk also in women, it would be important to ascertain whether the reduced susceptibility of hypertensive females to cerebrovascular diseases is related to a protection from the deleterious cerebrovascular effects of hypertension. Although recent evidence suggests that large cerebral arteries of female mice are less susceptible to the constriction produced by ANG II (7), it is unknown whether females are also protected from the alterations in CBF regulatory mechanisms induced by ANG II and whether this effect is related to ovarian hormones.

In this study we examined whether female mice are protected from the cerebrovascular dysregulation induced by ANG II. We found that the attenuation in functional hyperemia and endothelium-dependent relaxation produced by ANG II is observed in male, but not female, mice. The cerebrovascular protection is abolished by ovariectomy and reestablished by estrogen administration to ovariectomized (OVX) mice. An administration of estrogen to male mice reproduces the protective effects observed in females. The data provide evidence that females are relatively protected from the cerebrovascular dysfunction induced by ANG II and implicate estrogen in the mechanisms of this effect. The reduced susceptibility of the female cerebral circulation to ANG II raises the possibility that improved vascular function may contribute to the reduced stroke risk in hypertensive females.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
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General surgical procedures. All procedures were approved by the Institutional Animal Care and Use Committee of Weill Cornell Medical College and were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Studies were conducted in 2- to 3-mo-old C57BL/6J male and intact female mice (weight, 20–30 g; Jackson; Bar Harbor, ME). Mice were anesthetized with isoflurane (maintenance 2%) in oxygen, intubated, and artificially ventilated (SAR-830; CWE; Ardmore, PA) (11, 12, 19, 20). The femoral artery was cannulated for recording mean arterial pressure (MAP) and for collection of blood samples. The femoral vein was used for ANG II administration. Rectal temperature was maintained at 37°C. After surgery, anesthesia was maintained only with urethane (750 mg/kg ip) and chloralose (50 mg/kg ip), and the depth of anesthesia was checked by testing corneal reflexes and motor responses to tail pinch (11, 12, 19, 20).

Monitoring of CBF. A portion of the parietal bone and the underlying dura were removed, and a 2 x 2-mm region of the cerebral cortex, including the whisker-barrel area, was superfused with a modified Ringer solution (37°C; pH: 7.3 to 7.4) (11, 12) (see Ref. 16 for composition). CBF was monitored in the window with a laser-Doppler probe (Vasamedics, St. Paul, MN). The outputs of the flowmeter and blood pressure transducer were connected to a computerized data acquisition system (MacLab; Colorado Springs, CO). CBF was expressed as percent increases relative to the resting level. Zero values were obtained after the heart was stopped by an overdose of isoflurane.

Ovariectomy, estrogen administration, and estrogen assay. Female mice underwent aseptic bilateral ovariectomy via a dorsal incision under isoflurane anesthesia 2 wk before the cerebrovascular effects of ANG II were tested.

Some OVX mice received estradiol benzoate (1 µg in 100 µl in sesame oil sc) (Sigma, St. Louis, MO) administered at 8:30 AM daily for 6 days (31). Other mice in the OVX group were treated with vehicle (sesame oil, 100 µl sc). Blood was collected at the end of the experiment, usually at 12:00–1:00 PM. Plasma estradiol levels were measured with a commercially available ELISA (Cayman Chemical, Ann Arbor, MI) according to the manufacturer's instructions (31).

Implantation of osmotic minipumps for sustained delivery of ANG II. Osmotic minipumps containing saline, phenylephrine (PE), or ANG II (ANG II acetate; Sigma) were implanted subcutaneously in mice under isoflurane anesthesia as described previously (19, 20). Systolic arterial pressure (SAP) was monitored daily in awake mice using tail-cuff plethysmography (19, 20). This method is suitable to detect large changes in SAP in the same subjects (22). Mice were accustomed to the tail-cuff apparatus for several days before pump implantation. ANG II was delivered at a rate of 2.74 mg·kg–1·day–1, which is comparable with the amount previously used by us and others (19, 20, 38). PE was delivered at a rate of 27.4 mg·kg–1·day–1, as previously reported (20). Seven days after implantation, mice were anesthetized and instrumented for assessment of cerebrovascular reactivity by laser-Doppler flowmetry (see General surgical procedures).

Experimental protocol. CBF recordings were started after MAP and blood gases were in a steady state (see supplemental table with the online version of this article). All pharmacological agents were dissolved in Ringer solution. The cranial window was first superfused with Ringer solution (vehicle), and CBF responses were recorded. The whisker-barrel cortex was activated for 60 s by stroking the contralateral facial whiskers (19, 20), and the evoked changes in CBF were recorded. The endothelium-dependent vasodilator acetylcholine (ACh; 10 µM; Sigma) or the endothelium-independent vasodilator adenosine (50 µM; Sigma) was then superfused on the exposed neocortex for 5 min. This concentration of adenosine was previously determined to elicit less than supramaximal responses (45). Adenosine increases CBF by acting directly on vascular smooth muscles (32). The CBF response to adenosine is not affected by ANG II-induced vascular oxidative stress and was used as a control for smooth muscle reactivity (12). The concentration of ACh used here increases CBF by endothelial mechanisms and independently of cholinergic effects on synaptic activity (46). After we tested CBF responses, saline or ANG II was administrated intravenously. The ANG II infusion was adjusted to elevate MAP by 20 to 25 mmHg gradually over 10 to 15 min until a stable increase was obtained (11, 12, 19, 20). At this time, the infusion rate was 0.25 ± 0.02 µg·kg–1·min–1, which produces elevations in plasma ANG II within the upper range of those produced by endogenous activation of the renin-angiotensin system in rodents (23). To avoid the confounding effects of changes in resting tone on the vascular responses tested, the concentration of ANG II infused was selected not to alter resting CBF (see Refs. 19 and 20 for discussion). CBF responses to whisker stimulation, ACh, and adenosine were tested again after 30–45 min of ANG II infusion.

Data analysis. Data are expressed as means ± SE, unless otherwise indicated. Multiple comparisons were evaluated by the ANOVA and Tukey's test. Differences were considered statistically significant for P < 0.05.


   RESULTS
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 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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Effect of acute administration of ANG II on cerebrovascular responses in male and female mice. Acute administration of ANG II produced comparable elevation in MAP in anesthetized male and female mice (Fig. 1A; P > 0.05; n = 5/group). There were no differences in the CBF response to whisker stimulation, ACh, or adenosine observed between male and intact female mice (Fig. 1, B–E; P > 0.05; ANOVA and Tukey's test; n = 5/group). In male mice, ANG II had no effect on resting CBF or on the increase in CBF produced by adenosine (P > 0.05), but it attenuated the increases in CBF evoked by whisker stimulation and ACh (Fig. 1, B–E; P < 0.05; n = 5/group). In female mice, ANG II failed to attenuate cerebrovascular responses to whisker stimulation and ACh (Fig. 1, C and D; P > 0.05 from saline; n = 5/group).


Figure 1
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  		Fig. 1. Cerebrovascular effect of acute intravenous administration of ANG II in male and female mice. A–E: effect of ANG II on mean arterial pressure (MAP; A); resting cerebral blood flow (CBF; B); and the CBF increase produced by whisker stimulation (C), acetylcholine (D), or adenosine (E). Data are means ± SE. *P < 0.05 from respective control before ANG II; ANOVA and Tukey's test; n = 5 mice/group. PU, perfusion units.

 
Effect of sustained administration of ANG II on cerebrovascular responses in male and female mice. We then investigated the cerebrovascular effects of the administration of ANG II or PE for 7 days using osmotic minipumps. Both ANG II and PE significantly elevated SAP in male mice at days 6 and 7 (P < 0.05 from vehicle; Fig. 2A). In female mice, ANG II and PE slightly elevated SAP, but the increase did not reach statistical significance (P > 0.05 from vehicle; Fig. 2B). Similarly, after anesthesia and instrumentation for CBF recording, MAP was elevated in males but not in females treated with ANG II or PE (Fig. 3A). Regardless of the treatment group, baseline CBF responses were the same in males and females (Fig. 3B). However, CBF responses to whisker stimulation and ACh were attenuated in male but not in female mice treated with ANG II (Fig. 3, C and D; P < 0.05; n = 5/group). Conversely, PE did not alter the increase in CBF induced by whisker stimulation, ACh, or adenosine in either sex (Fig. 3, C–E; P > 0.05).


Figure 2
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  		Fig. 2. A and B: time course of the effect of vehicle (saline), ANG II, or phenylephrine (PE) administrated over 7 days by subcutaneously implanted osmotic minipumps on systolic arterial pressure in male (A) and female (B) mice. *P < 0.05 from vehicle; ANOVA and Tukey's test; n = 5 mice/group.

 

Figure 3
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  		Fig. 3. Cerebrovascular effects of 7-day infusion of ANG II or PE in male and female mice using osmotic minipumps. A–E: effect of vehicle, ANG II, and PE on MAP (A); resting CBF (B); and CBF responses to whisker stimulation (C), acetylcholine (D), or adenosine (E). *P < 0.05 from vehicle; ANOVA and Tukey's test; n = 5 mice/group.

 
Effect of ovariectomy and estrogen administration on cerebrovascular responses with acute ANG II administration in female mice. Since the above studies were performed on intact female mice with varying levels of ovarian hormones, we sought to determine whether the lack of cerebrovascular effect of ANG II was related to estrogen. To this end, female mice were subjected to ovariectomy and treated with estradiol or vehicle. Sham-operated mice served as controls. Ovariectomy significantly reduced plasma levels of estradiol (sham operated, 5.9 ± 0.3; OVX, 1.8 ± 0.5 pg/ml; P < 0.05; n = 5/group) (5, 31). In OVX mice, ANG II elevated MAP as in sham-operated intact controls (Fig. 4A) and did not affect resting CBF or baseline CBF responses to whisker stimulation, ACh, or adenosine (Fig. 4, B–E). However, administration of ANG II in OVX mice attenuated the CBF increase produced by whisker stimulation or ACh (P < 0.05) to a level comparable with that observed in male mice (compare Fig. 4, C and D with Fig. 3, C and D). We then examined whether estradiol administration could counteract the effects of ovariectomy. Estradiol administration increased serum estradiol (18.5 ± 2.3 pg/ml; P < 0.05 from OVX) without affecting the increase in MAP induced by ANG II or baseline CBF responses (Fig. 4, A and B). However, estradiol administration to OVX mice prevented the ANG II-induced attenuation of the CBF response evoked by whisker stimulation or ACh (Fig. 4, C and D).


Figure 4
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  		Fig. 4. Cerebrovascular effect of acute intravenous administration of ANG II in sham-operated mice (Sham) or ovariectomized mice (OVX) receiving vehicle or estradiol benzoate (E2). A–E: effect of ANG II on MAP (A); resting CBF (B); and CBF responses to whisker stimulation (C), acetylcholine (D), or adenosine (E). *P < 0.05 from vehicle; ANOVA and Tukey's test; n = 5 mice/group.

 
Effect of estrogen on cerebrovascular responses with acute ANG II administration in male mice. Since CBF responses in OVX females and males were identical, we examined whether exogenous estrogen was able to counteract the cerebrovascular effects of ANG II also in male mice. Estradiol or vehicle (sesame oil) was administered to male mice according to the same dosing regimen used in female mice. Estradiol did not affect resting MAP or the CBF increases produced by whisker stimulation, ACh, or adenosine in the absence of ANG II (Fig. 5, A–D). Furthermore, estradiol did not affect the increase in MAP induced by ANG II or the CBF responses to adenosine (Fig. 5, A–D). However, estradiol completely reversed the ANG II-induced attenuation of the cerebrovascular responses to whisker stimulation or ACh (Fig. 5, B and C).


Figure 5
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  		Fig. 5. Effect of acute intravenous administration of ANG II in intact male mice treated with vehicle or E2. A–D: effect of on ANG II on MAP (A) and on the CBF responses to whisker stimulation (B), acetylcholine (C), or adenosine (D). *P < 0.05 from respective control before ANG II infusion; ANOVA and Tukey's test; n = 5 mice/group.

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We have demonstrated that the powerful effects of ANG II on cerebrovascular reactivity seen in male mice are not observed in female mice. Thus ANG II does not alter the increase in CBF induced by neural activity or by the endothelium-dependent vasodilator ACh in female mice. The sex-specific effects of ANG II on cerebrovascular responses were observed both in acute (30 min) and chronic (7 days) ANG II administration protocols. The female protection against the cerebrovascular effects of ANG II was abolished by ovariectomy and reinstated by estrogen administration to OVX mice. Administration of estrogen to male mice also prevented the effects of ANG II on functional hyperemia and CBF response to ACh. These observations, collectively, indicate that female mice are less susceptible to the cerebrovascular effects of ANG II and that estrogen is involved in this effect.

Exclusion of potential sources of artifacts. The sex differences in the cerebrovascular effects of ANG II cannot be attributed to variations in body temperature or arterial blood gases because these parameters were carefully controlled and did not differ among the groups of mice studied. A time-dependent deterioration of the preparation cannot explain the findings because we have previously demonstrated that, in the absence of ANG II, cerebrovascular responses are stable over the duration of the experiment (12). In addition, changes in resting cerebrovascular tone cannot be responsible for the observed differences because we administered a dose of ANG II that does not alter resting CBF (20). Similarly, differences in MAP between male and female mice are unlikely to play a role because we have previously demonstrated that the elevation in MAP does not contribute to the cerebrovascular effects of ANG II in this model (20). Furthermore, in the acute administration paradigm, ANG II was not effective in female mice despite increases in MAP compared with that of males. Therefore, the findings of the present study cannot be due to an instability of the preparation or to a difference in MAP or resting tone. We found that female mice were less susceptible to develop hypertension during infusion of ANG II for 7 days. The small increases in SAP observed in female mice did not reach statistical significance due to the inherent variability of the tail-cuff method used to monitor SAP (22). However, such variability is not a source of concern because accurate MAP measurements were obtained later using an indwelling catheter when cerebrovascular reactivity was studied. In addition, our finding that conscious female mice are less susceptible to hypertension during chronic infusion of ANG II has also been reported in studies in which MAP was measured by telemetry implants (43).

CBF responses to whisker stimulation and ACh are not sexually dimorphic. We found no sex differences in the increase in CBF elicited by whisker stimulation, ACh, or adenosine. Furthermore, ovariectomy with or without estrogen administration had no effect on these cerebrovascular responses. These findings are in agreement with previous reports that resting CBF and the increase in CBF produced by ACh or neural activity do not differ in male, female or OVX rodents (1, 14, 21, 39). Similarly, no differences in resting CBF were observed in different estrous states (3). However, studies in isolated cerebral vessels have demonstrated that estrogen decreases vascular tone, an effect attributed to endothelial nitric oxide (NO) and cyclooxygenase-dependent mechanisms (8, 29). Furthermore, the pial arteriolar response to topical application of ACh in vivo is reduced in rats tested 4 wk after ovariectomy, a time interval longer than that used in the present study (42). The reasons for these discrepancies remain unclear and suggest a higher level of complexity in the cerebrovascular effects of reproductive hormones.

Estrogen administration counteracts the effects of ovariectomy on ANG II-induced vascular dysfunction. We found that ovariectomy made the female mice vulnerable to the cerebrovascular effects of ANG II, indicating that gonadal steroids are involved in the protection from the cerebrovascular effects of ANG II in females. To determine whether estrogen plays a role, estrogen was administered to OVX mice. Estrogen administration increased plasma estrogen levels and counteracted the cerebrovascular effects of ANG II, indicating that estrogen confers protection against the cerebrovascular actions of ANG II. Our administration method provided estrogen levels comparable with those of female mice between diestrus and proestrus (5). There are several protocols for estrogen replacement, which all have strengths and weaknesses (6). Although these methods produce a more or less stable elevation of estrogen levels, they fail to mimic the cyclic variations of both estrogen and progesterone occurring in normally cycling females (4, 24). Despite these reservations, our findings provide initial evidence that estrogen is involved in the protection from the cerebrovascular effects of ANG II observed in female mice. This conclusion is reinforced by our findings that the administration of estrogen to male mice prevents the deleterious effects of ANG II on the cerebrovascular reactivity to whisker stimulation and ACh. However, the specific estrogen receptors (ERs) responsible for the attenuation of the cerebrovascular effects of ANG II remain to be identified. ER-{alpha} and -β are present in systemic and cerebral blood vessels and have been implicated in cardiovascular and cerebrovascular regulation (36, 47) (see Ref. 6 for a review). ER-β null mice develop arterial hypertension and dysregulation of vascular smooth muscle function (47). On the other hand, ER-{alpha} has been implicated in the protection from ANG II-induced hypertension in female mice (44) and in the cerebrovascular effects of estrogen as well (9). Therefore, both receptors could be involved in the protection from the cerebrovascular effects of ANG II observed in female mice. Studies using selective agonists and/or null mice are needed to identify the role of specific ERs.

Potential mechanisms of the sexual dimorphism of the cerebrovascular effects of ANG II. Previous studies from this and other laboratories have shown that the effects of ANG II on cerebrovascular responses are mediated by ROS produced by a NOX-2-containing NADPH oxidase via activation of ANG II type 1 (AT1) receptors (11, 19, 20). Recent data suggest that ROS react with NO to form peroxynitrite, which, in turn, is responsible to the cerebrovascular dysfunction induced by ANG II (12). NADPH oxidase expression, activity, and function are more prominent in cerebral blood vessels than in systemic vessels (27). Interestingly, the expression of selected subunits of NADPH oxidase and NADPH oxidase activity is less in female than in male cerebral blood vessels (26). Therefore, the reduced cerebrovascular response to ANG II in females could be related to a reduction in NADPH expression and to the attendant reduction in ROS production. Although NOX-2 is not reduced in large cerebral vessels of female rats (26), it remains to be established whether there is a sex difference in the distribution of NOX isoforms in the pial arterioles mediating the CBF changes in our model. In addition, the reduced susceptibility of females to the cerebrovascular effects of ANG II could be due to estrogen-dependent modulation of AT1 receptor levels (28). This possibility also needs to be explored. Alternatively, estrogen could reduce ROS by acting as a free-radical scavenger (6) or could increase NO production (6), which is potentially vasoprotective. However, when we consider that the deleterious cerebrovascular effects of ANG II are mediated by peroxynitrite (12), such an increase in NO production could be protective only if it does not lead to an increase in peroxynitrite. Finally, the role of other peptides derived form angiotensin metabolism, such as ANG(1-7), in the sex-specific effects of ANG II remains to be defined (13).

We also found that the acute administration of ANG II elicited comparable elevations in MAP in male and female mice, whereas chronic administration did not elevate MAP in females. The reasons for such difference are not clear. One possibility is that changes in sympathetic activity and baroreflex control of heart rate during chronic infusion of ANG II may contribute to sex differences in the development of hypertension. This possibility is supported by the observation that estrogen modulates baroreceptor function in mice (30).

Conclusions. In conclusion, we have demonstrated that female mice are relatively spared from the cerebrovascular dysfunction induced by ANG II. Thus females are less susceptible to the ANG II-induced attenuation of the increase in CBF induced by neural activity or the endothelium-dependent vasodilator ACh. The protection is abolished by ovariectomy and reinstated by estrogen administration, pointing to estrogen as the ovarian hormone responsible for these effects. Such increased resistance to neurovascular dysfunction may provide a previously unrecognized mechanism for the protection from stroke and vascular cognitive impairment observed in hypertensive women.


   GRANTS
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 MATERIALS AND METHODS
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C. Iadecola is the recipient of a Javits award from National Institute of Neurological Disorders and Stroke. This study was supported by National Heart, Lung, and Blood Institute Grant HL-18974.


   ACKNOWLEDGMENTS
 
H. Girouard holds a fellowship from the Canadian Institute in Health Research.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. Iadecola, Div. of Neurobiology, Weill Cornell Medical College, 411 E. 69th St., New York, NY 10021 (e-mail: coi2001{at}med.cornell.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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