Published online before print October 10, 2005, doi: 10.1161/01.HYP.0000185648.48498.c1
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(Hypertension. 2005;46:1163.)
© 2005 American Heart Association, Inc.
Original Articles |
Gender-Specific Alteration of Adrenergic Responses in Small Femoral Arteries From Estrogen Receptor-ß Knockout Mice
From the Departments of Obstetrics and Gynecology (L.L., L.A., K.K.) and Medical Nutrition (J.-Å.G.), Institution for Clinical Science, Intervention, and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Huddinge Campus, Stockholm, Sweden; and Maternal and Fetal Research Unit (L.P.), St Thomas’s Hospital, Kings College London, United Kingdom.
Correspondence to Karolina Kublickiene, MD, PhD, Institution for Clinical Science, Department of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital-Huddinge Campus, 14186 Stockholm, Sweden. E-mail karolina.kublickiene{at}klinvet.ki.se
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Abstract |
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Estrogen receptor-ß knockout mice become hypertensive as they age, and males have a higher blood pressure than females. We hypothesized that the absence of estrogen receptor-ß may contribute to development of cardiovascular dysfunction by modification of adrenergic responsiveness in the peripheral vasculature. Small femoral arteries (internal diameter <200 µm) were isolated from estrogen receptor-ß knockout and wild-type mice and mounted on a wire myograph. Concentration-response curves to phenylephrine and norepinephrine were compared and the contribution of adrenoceptor subtypes established using specific agonists and antagonists. The involvement of endothelial factors in the modulation of resting tone was also investigated and immunohistochemical analysis used to confirm the presence or absence of estrogen receptor expression. Compared with wild type, arteries from estrogen receptor-ß knockout male, but not female, mice demonstrated gender-specific enhancement of the response to phenylephrine (
1-adrenoceptor agonist), which was accompanied by elevated basal tension attributable to endothelial factors. Contractile responses to the mixed adrenoceptor agonist norepinephrine did not differ significantly between estrogen receptor-ß knockout and wild type; however, ß-adrenoceptor inhibition unmasked an enhanced underlying 1-adrenoceptor responsiveness in estrogen receptor-ß knockout males. ß-adrenoceptor–mediated dilatation was also enhanced in estrogen receptor-ß knockout versus wild-type males. We suggest that estrogen receptor-ß modifies the adrenergic control of small artery tone in males but not in females.
Key Words: gender • endothelium • estrogen • arteries • vasoconstriction • adrenergic receptor agonists
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Introduction |
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Endogenous estrogens are considered to play an important role in cardiovascular homeostasis. Through occupancy of estrogen receptors (ERs)
(ER) and ß (ERß), estrogens target genes that contribute to the regulation of vascular tone, the lipid profile, redox status, and vascular structure. However, the relative role of each ER subtype in cardiovascular responses to estrogens remains poorly understood.1
ER and ERß are expressed in the endothelium and in vascular smooth muscle (VSM), but expression of the ER subtypes is gender and vascular bed dependent.2,3 The explicit role of ER subtypes in the cardiovascular system, particularly in relation to regulation of vascular tone, has been difficult to assess because of the lack of specific ER subtype antagonists or agonists. The development of genetically modified animals in which one or other of the ERs is disrupted provides a useful alternative strategy for investigation. Zhu et al4 reported that absence of ERß leads to age-dependent hypertension in both genders of mice, and that blood pressure in males was higher. However, no mechanisms that could explain gender-related differences in hypertension were proposed,4 and it is unlikely that the altered contractile function observed in the aorta of the ERß knockout (ERßKO) mice4 would predispose to the development of hypertension because the aorta does not contribute to peripheral resistance.
Hypertension is often associated with altered adrenergic responses in the vasculature. The prevalence and interaction between adrenoceptors (ARs) responsible for either constriction (1-AR and 2-AR on VSM) or relaxation (ß-AR on VSM and endothelial 2-AR or ß-AR) can predispose toward altered peripheral resistance and raised blood pressure.5–9 Moreover, gender-related differences in adrenergic responses have been reported in hypertensive and normotensive subjects.10–17
This study was designed to test the hypothesis that hypertension and gender-related differences in blood pressure observed in aging ERßKO mice could be consequent to modified adrenergic reactivity in peripheral small arteries. To avoid potential sequelae of raised blood pressure in older animals, we compared contractile responses to phenylephrine (PE; selective 1-AR agonist) and norepinephrine (NE; mixed -AR and ß-AR agonist) in small femoral arteries isolated from ERßKO and age-matched wild-type (WT) mice at an age before hypertension development. The relative roles of 2-AR or ß-AR in the NE response were assessed using specific antagonists. The effects on these responses of NO synthase (NOS) and cyclooxygenase (COX) inhibition were also evaluated. Endothelial function was also assessed by determining endothelium-dependent constrictor responses subsequent to NOS and COX inhibition, as well as relaxation after administration of the ß-AR agonist isoproterenol (ISO).
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Methods |
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Mice and Small Artery Preparation
Animal care and procedures performed were in accordance with guidelines on conduction of animal experiments issued by the Swedish National Board for Laboratory Animals. The study was also approved by the ethical committee of animal experiments at the Karolinska Institutet, Stockholm, Sweden. Experiments were performed on age-matched (14 to 22 weeks of age) male and female WT mice (ERß+/+; C57BL/6J) and homozygous mutant mice lacking the gene for ERß (ERß–/–; ERßKO).18 The mean body weight of males was 31.0±0.9 g (WT; n=15) and 32.5±0.7 g (ERßKO; n=16) compared with 23.0±0.5 g (WT; n=8) and 25.6±1.5 g (ERßKO; n=8) for females.
Animals were killed by CO2 inhalation. The distal femoral arteries were dissected in ice-cold physiological salt solution (PSS) under a stereomicroscope and used either for immunohistochemistry or functional study.
Immunohistochemical Analysis
Paraffin sections (4 µm thick) of WT and ERßKO mice femoral arteries were immunostained with polyclonal rabbit antibodies against mouse ER and ERß (1:100 dilution; Santa Cruz Biotechnology). The specificity of these antibodies has been described previously.19,20 Negative control sections for ER and ERß were incubated with nonimmune goat IgG (SDS). Human endometrial tissue section served as a positive control for ER21,22 and ovarian tissue for ERß.21
Wall Tension Measurement
The distal femoral arteries (diameters: male WT 174±5 µm and ERßKO 183±8 µm; female WT 172±5 µm and ERßKO 161±5 µm) were mounted on a 4-chamber Danish Myotechnology M610 wire myograph as described previously.23 Arteries that were precontracted with 1 µmol/L NE and did not achieve 
50% relaxation in response to 1 µmol/L of acetylcholine (ACh) were excluded from the study.
Experimental Protocols
Contractile Responses
Cumulative concentration-response curves were constructed for either PE (selective agonist of 1-AR 10–8–5x10–5 M), NE (nonselective agonist of AR 10–8–5x10–5 M) or the thromboxane mimetic (U46619 10–9–10–7 M) before and after incubation with the NOS inhibitors Nw-nitro-L-arginine methyl ester (L-NAME; 100 µmol/L) plus Nw-nitro-L-arginine (L-NNA; 300 µmol/L) and the COX inhibitor indomethacin (Indo; 10 µmol/L). The concentration of NOS inhibitors was sufficient to inhibit NO synthesis because endothelium-dependent relaxation to ACh (10µmol/L) was not further reduced by addition of the selective guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one in L-NAME–treated vessels (39.9±6.8 versus 42.5±5.0%; n=4). The degree of increased resting tone in the arteries after incubation with L-NAME+L-NNA+Indo was considered to reflect basal synthesis of endothelium-derived vasoactive substances.
Because constriction to PE, but not to NE, was enhanced in arteries from ERßKO versus WT males, we sought to clarify the mechanisms responsible. In separate arteries, concentration-response curves to NE (10–8–10–5 M) were obtained before and after preincubation (20 minutes) with yohimbine (1 µmol/L) or pronethalol (1 µmol/L) to block 2-adrenergic or ß-adrenergic receptors, respectively.
ISO-Induced Relaxation
A cumulative concentration-response curve to the ß-AR agonist ISO (10–8–3x10–5 M) was obtained in arteries from male animals after preconstriction with PE at a concentration sufficient to evoke a sustained maximal response (10 µmol/L).
Statistical Analysis
Differences in responses between groups were determined by comparing concentration-response curves using a 2-way repeated-measures ANOVA, in which substance concentration and group membership were used as a within-subject factor and a between-subject factor, respectively. The interaction effect between concentration and group membership tested the hypothesis that the concentration-response curves differ between the groups. Paired Student’s t test was used to compare pEC50 value before and after incubation with substances in arteries from different protocols. Data are presented as mean±SEM; n represents the number of animals; significance was accepted at P<0.05.
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Results |
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Immunohistochemical Analysis
ER
and ERß were localized within endothelium and VSM. No staining for ERß was observed in arteries from ERßKO female or male mice (Figure 1).
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) and male (
) WT and ERßKO mice. All images are x40.
Vasoconstrictor Responses
PE, NE, and U46619 evoked concentration-dependent contractile responses in isolated arteries from WT and ERßKO mice. Sensitivity was highest to U46619 in both genotypes (Table).
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WT Mice
Sensitivity to NE was greater than that to PE (Table; Figure 2), but there were no gender-related differences in sensitivity to any vasoconstrictor (Table). In males, NOS and COX inhibition increased sensitivity to PE (Table), but in females, these inhibitors were without effect. Sensitivities to U46619 and NE were unaffected by L-NAME+L-NNA+Indo in male and female arteries.
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statistically significant difference between responses to NE and PE in arteries from ERßKO females. KPSS indicates high-potassium salt solution.
WT Versus ERßKO Mice
Enhanced responses to PE were observed in arteries from ERßKO (maximal tension response 2.3±0.1 mN/mm) versus WT males (1.8±0.1 mN/mm; Table; P<0.001; Figure 2a), but responses to NE (ERßKO 2.1±0.2 mN/mm versus 2.0±0.2 mN/mm for WT) and U46619 (ERßKO 2.6±0.3 mN/mm versus 2.4±0.2 mN/mm for WT) were not significantly different. In contrast to male WT mice in which NE responses were greater than PE, in ERßKO, sensitivity to PE was greater than NE (P<0.007; Table). There was no difference in PE-, NE-, or U46619-induced constriction between arteries from WT and ERßKO females. Arteries from ERßKO females showed significantly higher responses to NE compared with PE (P<0.005; Table; Figure 2b), and a greater contractile responsiveness to PE was evident in arteries from ERßKO males versus females (P<0.05; Figure 2b). Contractile responses to PE, NE, and U46619 in arteries from both male and female ERßKO were not significantly different before and after incubation with L-NAME+L-NNA+Indo (Table).
Influence of the Endothelium on Basal Tone
L-NAME+L-NNA+Indo–induced constriction revealed gender differences in endothelium-dependent modulation of basal tone in arteries from WT because the tone developed in females was significantly higher than in males (Figure 3). However, in ERßKO mice, the increase in tone was significantly higher in male than in female arteries (P<0.05; Figure 3). Moreover, contractions after administration of these inhibitors were more pronounced in ERßKO than in WT males (P<0.001; Figure 3), but no differences were observed between female genotypes (P=0.5; Figure 3).
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statistically significant difference between the response in arteries from females vs males. KPSS indicates high-potassium salt solution.
Role of AR Subtypes in Contractile Responses in Arteries From Male Mice
Yohimbine did not affect resting tension, whereas pronethalol induced a small but comparable rise in basal tone in arteries from both groups (ERßKO 4.7±1.4% versus WT 4.3±0.9%; P=0.9).
Contribution of 1-AR and 2-AR to Contractile Responses
Yohimbine reduced WT artery sensitivity to NE to a value similar to that observed for PE (pEC50 6.0±0.1 versus 6.0±0.1; P=0.8; Figure 4a). Sensitivity to NE in ERßKO mice was also significantly reduced by yohimbine (pEC50 5.65±0.05 versus 6.3±0.09; P<0.005; Figure 4b) but greater sensitivity to PE versus NE persisted (pEC50 6.8±0.1 versus 5.65±0.05; P<0.001; Figure 4b). Constriction to NE after preincubation with yohimbine remained lower in arteries from ERßKO versus WT mice (pEC50 5.65±0.05 versus 6.0±0.1; P<0.05).
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Role of ß-AR in Contraction to NE
Pronethalol (ß-AR inhibitor) did not alter the NE response in arteries from WT males (pEC50 6.7±0.1 with pronethalol versus 6.4±0.1 without; P=0.2) but markedly enhanced NE-induced contraction in arteries from ERßKO males (pEC50 6.3±0.09 before versus7.0±0.09 with pronethalol; P<0.001; Figure 4b) such that the response to NE after ß-AR blockade was not significantly different from that for PE (pEC50 7.0±0.09 for NE versus 6.8±0.1 for PE; P=0.2; Figure 4b). As would be anticipated, the concentration-response curve to NE in the presence of pronethalol showed a significant leftward shift in ERßKO versus WT males (pEC50 7.0±0.09 ERßKO versus 6.7±0.1 WT; P<0.05; Figure 4b).
ISO elicited relaxation only at the concentration range 10–6–3x10–5 mol/L in arteries from WT and ERßKO males, but the response was enhanced in ERßKO males versus WT (eg, at 10–5 mol/L 22±3% versus 18±2%; at 3x10–5 mol/L 27±3% versus 20±2%; P<0.05; n=5 each group).
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Discussion |
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This report, to our knowledge, represents the first observation of altered vasoconstrictor responses in the peripheral circulation of ERßKO mice, thus providing insight into the role of ERß in cardiovascular homeostasis. In contrast to studies in conduit vessels,4 investigations on small femoral arteries (ie, internal diameter <200 µm) as used in this study offer an opportunity to probe the mechanisms contributing to the control of peripheral vascular tone24 and provide information pertinent to the etiology of the hypertension we described previously.4 These arteries expressed ER
and ERß in WT animals, as detected by immunohistochemistry, whereas ERß, as expected, was undetectable in arteries from ERßKO animals.
The data imply a specific interaction between ERß and ARs, suggesting that expression of ERß may subdue responses to AR agonists in male but not female mice. Thus, we report that ERß deficiency is associated with enhanced responses to 1-AR stimulation in small femoral arteries from ERßKO compared with WT male mice. Although it may then seem surprising that responses to mixed -AR and ß-AR stimulation by NE were unaffected, the use of specific inhibitors of ß-ARs unmasked an increase in ß-AR–mediated dilatation in the ERßKO males. This apparent compensatory increase in dilator function may prevent an increase in peripheral adrenergic tone and so contribute to the preservation of normal blood pressure at the age studied. Because male ERßKO mice develop higher age-related hypertension,4 it is possible that this compensatory response is inadequate with age, and that altered adrenergic constrictor responses observed could later contribute to a rise in blood pressure. However, females seemed to be more resistant to an absence of ERß, at least with respect to the adrenergic control of vascular tone.
The increased 1-adrenergic reactivity in the arteries from ERßKO males is in accord with increased reactivity to PE observed previously in small cerebral arteries from ovariectomized (OVX) rats, which is also accompanied by elevation of blood pressure.25 Because responses to PE are similar in aortas from ERßKO and WT male mice,4 it would also appear that the observed defect is a characteristic of small arteries alone. Indeed, PE responses have also been shown to be similar in aortas from WT, ERßKO, and ERKO female mice after OVX and 17ß-estradiol supplementation.26
The gender specificity of the enhanced PE responsiveness observed in the ERßKO mice shares similarities with small arteries from spontaneously hypertensive rats (SHR), in which enhanced adrenergic stimulation and increased blood pressure have been demonstrated in males10 but not in females.15,27 After OVX, adrenergic nerve stimulation also increases in small arteries from SHR females as a result of an 1-AR–mediated response, whereas estrogen supplementation reversed this effect.15
Despite enhanced constriction to PE, the similarity of responses to NE in ERßKO and WT males suggested that ER-dependent modulation of ARs occurs to prevent enhanced NE constriction in ERßKO males. Whereas PE constricts solely via 1-AR on VSM cell, NE may modulate vasoconstriction via endothelial 2-AR and release of endothelium-derived factors,12,28,29 predominantly NO,30 the contribution of which decreases with diminishing artery size.31–33 Indeed, we found no evidence for endothelial 2-AR–mediated dilatation in small femoral arteries from either ERßKO or WT because NE responses were not significantly different before and after incubation with endothelial NOS and COX inhibitors.
With the use of yohimbine, we were able to identify contributions from both -AR subtypes (1, and 2) in NE-induced constrictor responses in male WT and ERßKO, but the NE response remained lower than the PE response in the ERßKO mice after yohimbine treatment (Figure 3), obviating a role for 2 AR. Instead, the relatively poor constriction to NE was the result of enhanced ß-AR–mediated relaxation because pretreatment with pronethalol (ß-AR inhibitor) increased NE-induced tone to a value similar to that generated by PE. This was confirmed by showing that dilatation to ISO (ß-AR agonist) was greater in ERßKO than WT males.
Three subtypes of ß-AR, ß1, ß2, and ß3, located on smooth muscle or endothelium have been identified.8 However, data from different subtype ß-AR knockout mice indicate that vascular relaxation of the murine femoral artery is solely dependent on the ß1-AR and it is endothelium independent.34 Endothelial independence is also supported by present study because concentration-response curves to NE were not significantly different before and after incubation with inhibitors of NOS and COX.
ß-AR–mediated relaxation has commonly been reported to decline with age because of the ß-AR desensitization that occurs with the age-related increase in endogenous catecholamine concentrations35 and male gender.36 An age-related loss of the compensatory ß-adrenergic response in ERßKO mice would therefore be likely to exacerbate or even initiate hypertension in these animals.
The mechanism responsible for the enhanced 1-adrenergic response leading to compensatory upregulation of ß-AR responsiveness in ERßKO males is unknown. Although endothelin-1 (ET-1) could play a role. ERß has been implicated in downregulation of the endothelin-converting enzyme gene,37and it has been shown that chronic ETA receptor inhibition in male SHR decreases 1-AR–induced constriction in isolated artery,38 whereas chronic ET-1 receptor activation increases ß-AR density.39,40
A potential support for the ET-1 hypothesis is provided by our observation of enhanced basal responsiveness to inhibition of endothelium-derived vasodilators in ERßKO mice (Figure 2). This was unlikely to be attributable to increased basal synthesis of endothelium-derived vasodilators because PE-, NE-, and U46619-induced constrictions were unaffected by inhibitors of NOS and COX. An increased basal tension after NOS inhibition in isolated small arteries has been attributed to the endogenous synthesis of ET-1,41,42 and increased basal tension in response to NOS inhibitor in cerebral arteries from OVX rats was associated with hypertension,25 which could be prevented by ETA inhibition.43 Therefore, observed AR abnormality could theoretically be achieved through increased basal ET-1 synthesis, but this requires verification by further investigations.
In conclusion, ERß seems to be more important for the adrenergic regulation of small artery tone in males than in females. ERß primarily targets the 1-adrenergic reactivity, followed by altered ß-AR responsiveness and changes in basal contribution of endothelium-derived factors. Together, these changes might initiate the development of hypertension in older ERßKO males.
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Acknowledgments |
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This work was supported by grants from the Swedish Heart and Lung Foundation, Lars Hiertas Minne Foundation, Centre of Gender-Related Medicine at Karolinska Institutet, and the Swedish Society of Medicine.
Received June 17, 2005; first decision July 8, 2005; accepted August 31, 2005.
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