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Endothelin-1-induced responses in isolated mouse vessels: the expression and function of receptor types

¹Department of Physiology and Cell Biology and ²Davis Heart and Lung Research Institute, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210

Submitted 9 December 2003 ; accepted in final form 7 April 2004

	ABSTRACT

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Mice have been increasingly used as models for investigating cardiovascular diseases. However, the responsiveness of mouse vasculature to endothelin (ET)-1 has not been clearly established. The goal of this study was to determine the role of ET receptors (ET_A and ET_B) in mouse vessels using isometric force measurements. Results showed that in the abdominal aorta ET-1 induced a concentration-dependent contraction (EC₅₀: 1.4 nM) with maximum reaching 89.5 ± 4.9% (10 nM) of that induced by 60 mM K⁺ [with nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME)]. However, in the thoracic aorta or the carotid artery, ET-1 was poorly effective. RT-PCR revealed that in the endothelium-denuded abdominal aorta, the PCR product for ET_B receptors was very low compared with ET_A. Similarly in tissues treated with L-NAME, the ET_B receptor-specific agonist sarafotoxin 6c (S6c; 100 nM) induced only a minimal contraction (<5%). Meanwhile, the ET_A antagonist BQ-123 (1 µM) completely inhibited the maximum ET-1 (10 nM) contractile response. Furthermore, we found that in the abdominal aorta that had not been treated with L-NAME, ET-1-induced contraction significantly decreased. However, in such specimens, S6c was unable to induce any relaxation on phenylephrine-induced contraction. These results indicate that the role of ET receptors differs considerably among mouse vessels. In the abdominal aorta, ET_A receptor mediates a potent vasoconstrictor response, whereas ET_B has, if any, only a minimal functional presence. Also, our data suggest that ET-1 might involve a NOS-dependent vasodilation in the abdominal aorta, which remains to be further defined.

endothelin_A receptor; endothelin_B receptor; vasoconstriction; nitric oxide synthase; vasodilation

In blood vessels, ET_A receptors are mainly located in the smooth muscle cells, and its activation by ET-1 leads to vasoconstriction (13, 14). In contrast, ET_B receptors exist both in the smooth muscle and in the endothelial cells (13, 14). While ET_B receptors present in the smooth muscle mediate vasoconstriction (13, 14, 24), those in the endothelial cell cause vasodilation via the release of endothelium-dependent relaxing factors, such as nitric oxide (NO) (12, 17, 23). However, it has been recently found that part of the depressor effect of ET_B receptor may be related to the clearance of ET-1 in the plasma (3, 5). In addition, ET_A receptor has also been suggested to be functional in the endothelial cells (11, 18, 19). Thus the regulation of vascular tone by ET receptors appears to involve a complicated mechanism that has yet to be fully understood.

Recently, genetically altered mice have been extensively used to study ET-1-mediated signaling in the regulation of cardiovascular function. Major mouse vessels from different vascular beds, such as the aorta and the carotid artery, have been the common targets for the pathological interventions to study the pathogenesis of cardiovascular diseases (1, 16). On the other hand, the responsiveness of these mouse vessels to ET-1 has not been clearly established. For example, in the thoracic aorta, ET-1 has been found to induce little contractile response (20). Therefore, there is a pressing need to determine whether ET receptors mediate the vasoconstrictor response differently among mouse vessels. In addition, ET_B receptors have been proposed to mediate a NO-dependent vasodilation in the mouse thoracic aorta (15). However, a previous study has demonstrated that in the mouse thoracic aorta, ET-1, which exhibits little vasoconstrictor effect, still elicits a contraction rather than a relaxation in the presence of an intact endothelium (20). Thus the role of ET_B receptors in endothelial NO release also needs to be further elucidated in mouse vessels.

Therefore, this study was designed to critically evaluate the ET-1-induced responses in major mouse vessels, including the thoracic aorta, the abdominal aorta, and the carotid artery, employing isometric force measurements. We found that among vessels studied, the mouse abdominal aorta exhibits a potent vasoconstrictor response to ET-1. Then, the function of ET_A and ET_B receptors in the abdominal aorta was further determined with RT-PCR and receptor-specific agonist or antagonist.

	MATERIALS AND METHODS

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Solution and chemicals. The ionic composition of physiological saline solution (PSS) was as follows (in mM): 123 NaCl, 4.7 KCl, 15.5 NaHCO₃, 1.2 KH₂PO₄, 1.2 MgCl₂, 1.25 CaCl₂, and 11.5 D-glucose. The 60 mM K⁺-PSS (K⁺) was prepared by replacing an equal molar of NaCl with KCl. Chemicals such as ET-1, the ET_B agonist sarafotoxin 6c (S6c), ACh, phenylephrine (PE), the ET_A antagonist BQ-123, and N-nitro-L-arginine methyl ester (L-NAME) were purchased from Sigma (St. Louis, MO). Other chemicals were also of the highest grade commercially available.

Animals and tissue preparation. Male C57/BL6J mice (8–12 wk) purchased from Jackson Laboratory were euthanized by 95% CO₂ inhalation, in accordance with animal use protocol of the Animal Research Ethics Committee of The Ohio State University. Tissues including the thoracic aorta, the abdominal aorta, the carotid artery, and the trachea were excised rapidly and placed in ice-cold PSS. The fat and the adventitia were mechanically removed under a binocular microscope. Then, the vessels and the trachea were cut transversely into 1.0-mm-wide rings. These procedures were performed at room temperature.

Isometric force measurement. The method of isometric force measurement is described elsewhere (27, 28). Briefly, the vascular or tracheal ring was mounted onto two tungsten wires in a 37°C water-circulating tissue bath filled with PSS, by passing the tungsten wires through the lumen of tissue specimen. One of the wires was fixed, and the other was connected to a force transducer (AE 801, Horten, Norway). During the equilibration period, tissues were stimulated with 60 mM K⁺ every 15 min (5 times), and the resting tension was increased in a stepwise manner. After the equilibration, the resting tension was adjusted to 300 mg for the vascular rings, and 200 mg for tracheal specimens, at which the maximal 60 mM K⁺ response was obtained.

Detection of ET receptor mRNAs in mouse abdominal aorta. The tissues were prepared as described above with the exception that they were not cut into rings. Vessels were cut open, and then the endothelial cells were removed by wiping with a cotton swab under a binocular microscope followed by washes until no trace of endothelium was detected. RNA preparation and RT-PCR were performed according to the manufacturer's manual using an Absolutely RNA RT-PCR Miniprep Kit (Stratagen, La Jolla, CA). Primers for ET receptors were as follows: 5'-ATGGTGGGGAACGCAACTCTACTA-3' (PCR sense) and 5'-GACGCTGTTTGAGGTGCTCACTAA-3' (RT and PCR antisense) for the ET_A receptor and 5'-GGGTT CCAAAATGGACAGTAG-3' (PCR sense) and 5'-CTCCAAGGACTGCTTTTCCTCAAA-3' (RT and PCR antisense) for the ET_B receptor. RT reaction was performed using 200 ng of total RNA in a volume of 20 µl. The protocols for PCR were as follows: 94°C for 30 s, 60°C for 60 s, and 72°C for 60 s (28–30 cycles as indicated). The expected sizes of PCR products were 622 bp for ET_A and 608 bp for ET_B. To determine the specificity of RT-PCR reactions, the PCR products were digested with 10 units of BamHI (NEB, Beverly, MA) according to the manufacturer's instruction. This treatment yields fragments of 310 and 312 bp for ET_A and 215 and 393 bp for ET_B according to the mouse cDNA sequences. The PCR products were separated with 2% agarose gel and visualized with ethidium bromide staining.

Experimental protocols. The physiological studies were conducted in blood vessels with intact endothelium at 37°C. In all experiments, an agonist was used only once in each specimen. Unless otherwise indicated, the agonist was administered 15 min after the final 60 mM K⁺ contraction had been relaxed with PSS. The force development caused by an agonist was expressed as a percentage of that obtained with 60 mM K⁺, assuming the value in the PSS (5.9 mM K⁺) and 60 mM K⁺ to be 0 and 100%, respectively. In certain experiments, 1 mM of the NO synthase (NOS) inhibitor L-NAME was added 5 min before an agonist was applied to eliminate the endothelial NO (27, 28). The effect of an agent to induce endothelium-dependent relaxation was examined on PE-induced contractions in vessels that had not been treated with L-NAME. The extent of the force change was expressed as a decrease or increase of force in a percentage of that induced by 60 mM K⁺.

Data analysis. The EC₅₀ value, a concentration at which 50% of maximum response was obtained, was determined from the concentration-response curves fitted to a four-parameter logistic model (7). Data are expressed as means ± SE. Student's t-test was used to determine the statistical significance. P < 0.05 was considered to indicate statistical significance.

	RESULTS

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ET-1-induced contractile response in mouse vessels. The effects of ET-1 on major mouse vessels have not been explored in detail. To determine how different mouse vessels respond to ET-1, isolated vessels including the abdominal aorta, the thoracic aorta, and the carotid artery were studied using isometric force measurements. Because ET-1 might mediate a concomitant endothelial NO release (14, 17, 23), the contractile response was evaluated in the presence of 1 mM L-NAME, which has been previously shown to abolish the endothelium-dependent relaxation induced by ACh in major mouse blood vessels (6, 28).

In the abdominal aorta, 60 mM K⁺ induced a contraction of 341 ± 15 mg. As shown in Fig. 1A, in response to 0.1, 1, 10, and 100 nM ET-1 stimulation, the mouse abdominal aorta developed a contraction of 0 ± 0, 36.5 ± 3.4, 89.5 ± 4.9, or 88.6 ± 4.1%, respectively, compared with that of 60 mM K⁺. Accordingly, the EC₅₀ value and the maximum response concentration were obtained at 1.4 nM and 10 nM, respectively. In addition, as demonstrated in Fig. 1B, the maximum contractile response induced by 10 nM ET-1 showed a sustained property similar to those seen in other species (24).

View larger version (14K): [in this window] [in a new window]   Fig. 1. Endothelin (ET)-1-induced contractile response in the mouse abdominal aorta. A: concentration-response curves of ET-1 in mouse abdominal aorta. ET-1 was used only once in each specimen and was administered 5 min after the application of 1 mM N-nitro-L-arginine methyl ester (L-NAME). The force development was expressed as a percentage compared with that induced by 60 mM K+. The values are expressed as means ± SE (n = 4–5). B: representative recordings showing the maximum contractile response induced by 10 nM ET-1 in the presence of L-NAME.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Representative traces showing the maximum contractile response induced by 10 nM ET-1 in the thoracic aorta (A) and in the carotid artery (B) in the presence of 1 mM L-NAME.

View larger version (51K): [in this window] [in a new window]   Fig. 3. Detection of ET receptor mRNAs with RT-PCR in the endothelium-denuded mouse abdominal aorta. Lanes 1 and 2: the level of PCR product amplified (30 cycles) from mRNA of ETA (622 bp, lane 1) or ETB receptor (608 bp, lane 2). Lanes 3 and 4: an enzymatic analysis of PCR products (30 cycles) for ETA (lane 3) and for ETB (lane 4) receptors with BamHI, which was expected to produce fragments of 310 and 312 bp and those of 215 and 393 bp, respectively. M, 100-bp ladder size makers (top to bottom: 1,000–100 bp).

View larger version (16K): [in this window] [in a new window]   Fig. 4. Effect of ET receptor type-specific agonist or antagonist in the mouse abdominal aorta. A: representative recordings demonstrating the contractile responses induced by the ETB receptor-specific agonist sarafotoxin 6c (S6c) in the mouse abdominal aorta (top) and the trachea (bottom). B: representative trace (from 3 identical experiments) showing the effect of ETA receptor antagonist BQ-123 on ET-1-induced contractile response.

View larger version (20K): [in this window] [in a new window]   Fig. 5. Effect of nitric oxide synthase activity on ET-1-induced response. A: summary of the contractile responses induced by different concentrations of ET-1 in the abdominal aorta in the presence (open bars) and in the absence (hatched bars) of 1 mM L-NAME (n = 4–5). B: summary of contractile responses induced by 10 nM ET-1 in the presence (open bars) and in the absence (hatched bars) of 1 mM L-NAME (n = 3–4) in the thoracic aorta (TA) and the carotid artery (CA). The force development was expressed as a percentage compared with that induced by 60 mM K+. The values are expressed as means ± SE. * P < 0.05.

View larger version (14K): [in this window] [in a new window]   Fig. 6. Representative recordings illustrating the effect of ETB receptor agonist S6c (100 nM) on 0.3 µM (A) and 1 µM (B) phenylephrine (PE)-precontracted mouse abdominal aorta. Top panels in A and B are controls.

	DISCUSSION

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An important finding of this study is that ET-1 induces a potent vasoconstrictor response in the mouse abdominal aorta. As demonstrated by the concentration-response curve obtained with the presence of NOS inhibitor L-NAME, ET-1-induced contractile response in the mouse abdominal aorta is as potent as those in human vessels, such as saphenous vein graft (12). Thus it is clear that ET receptors play a significant role in mediating the vasoconstriction in mice. However, ET-1-induced responses are not uniform among major mouse vessels. In the thoracic aorta, we found that 10 nM ET-1 only induced a contraction of 7.8% compared with that of 60 mM K⁺, similar to the results previously reported on the endothelium-denuded tissue specimens (20). In addition, we found that the carotid artery, a peripheral mouse vessel, is also poorly responsive to ET-1 (8.3% as a percentage of that induced by 60 mM K⁺). These results may suggest that the vasoconstrictor role of ET receptors varies considerably among different mouse vessels.

The above results prompt us to determine the ET receptor type(s) mediating the contractile response in the abdominal aorta. As shown by RT-PCR amplification, mRNAs of both ET receptors are expressed in the endothelium-denuded specimens. Interestingly, the PCR product for ET_B was in very low abundance (Fig. 3). We suspect that ET_B receptors may not have a major role in ET-1-induced contraction. However, the RT-PCR reactions were performed using different primers. In addition, there is a possibility of endothelial contamination. Therefore, the functional involvement of receptor types was further determined with a receptor-specific agonist or antagonist. As shown in Fig. 4A, the ET_B receptor-specific agonist S6c (100 nM) induced only a minimal contractile response in the presence of L-NAME. However, the specific ET_A antagonist BQ-123 (1 µM) completely antagonized the maximum contractile response induced by 10 nM ET-1 (Fig. 4B). These results altogether indicate that ET_A, but not ET_B, is the predominant vasoconstrictor ET receptor in the mouse abdominal aorta, which concurs with reports on several rat as well as human vessels (5, 8, 12, 21, 22, 25).

Also of interest is our finding that ET-1-induced contraction in the abdominal aorta was significantly decreased when L-NAME was omitted from the medium (Fig. 5A). This may suggest an existence of NOS-dependent vasodilation that antagonized part of the vasoconstrictor effect of ET-1. However, in the thoracic aorta and the carotid artery, which exhibited a minimal contractile response to ET-1, the effect of this NOS-dependent vasodilation is not detectable (Fig. 5B), suggesting that the basal NO release may not significantly modify the contractility of isolated mouse vessels. In addition, we have recently found that the response of mouse vessels (including the abdominal aorta) to ANG II was not affected by L-NAME (28). Therefore, the NOS-dependent vasodilation might be specifically elicited by ET-1 stimulation, consistent with the endothelial NO-releasing effects of ET-1 as generally proposed (14, 17, 23). However, we were unable to remove the endothelial cells in the mouse vascular rings efficiently to reach a conclusion that the NOS-dependent vasodilation was originated from the endothelium.

In contrast to ET-1, the ET_B receptor-specific agonist S6c, which has only a minimal vasoconstrictor effect on the mouse abdominal aorta, was unable to cause a vasodilating response in tissue with intact endothelial function (Fig. 6). This may suggest that ET_B receptor does not mediate a significant extent of endothelium-dependent relaxation in the abdominal aorta. Thus the divergent effects of ET-1 in the abdominal aorta might have been mediated by ET_A receptor, which seems contradictory to the generally proposed role of ET_B receptor in the endothelium. However, it must be noted that ET_A receptor has been found to exist in the endothelial cells of certain vessel types (11, 18). Also, the ET_A receptor has been demonstrated to mediate the Ca²⁺ homeostasis in endothelial cells of porcine aortic valves in situ (19). Thus ET_A receptors could also mediate the endothelial NO release, considering that the endothelial NOS is a Ca²⁺-calmodulin-activated enzyme (9). However, we were unable to document an ET_A receptor-mediated relaxation. In addition, other unclassified ET receptors (non-A and non-B receptors) might also exist (2). Therefore, the exact mechanism for the NOS-dependent vasodilation that compromised ET-1-induced contractile response in mouse abdominal aorta requires further investigation.

The above results suggest that the ET_B receptor may not be significantly involved in mediating vasoconstriction or endothelium-dependent vasodilation in the mouse abdominal aorta. However, ET_B receptors have been found to mediate the vasoconstriction in certain mouse vessels. For example, both ET_A and ET_B receptors have been found to mediate contraction in the perfused renal or mesenteric arteries (4). Thus the involvement of ET receptor types in vasoconstrictor response also appears to differ depending on the location of a vessel. On the other hand, there has been little direct evidence to indicate that ET_B receptor mediates endothelium-dependent relaxation in mice, as those observed on porcine coronary and pulmonary arteries (17, 23). We noted that the ET_B receptor S6c had been reported to produce a concentration-dependent relaxation in the mouse thoracic aorta (15). However, we were unable to obtain such a response using a similar experimental protocol (data not shown). Instead, we found that ET-1 induced a subtle contraction with or without L-NAME (Fig. 5B), which is similar to a report performed on specimens with or without endothelium (20). As a result, the role of ET_B receptor in mediating endothelium-dependent relaxation in mice has yet to be further elucidated.

In summary, in this study we examined ET-1-induced responses in isolated mouse vessels using isometric force measurements. Our data demonstrate that the role of ET receptors varies considerably among different mouse vessels. In the abdominal aorta, ET_A receptor mediates a potent vasoconstrictor response, while ET_B has, if any, a minimal functional presence. In addition, in the abdominal aorta, ET-1 might also involve a NOS-dependent vasodilation, which remains to be further defined.

	GRANTS

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This work was supported by National Heart, Lung, and Blood Institute (NHLBI) Grant HL-38355 to M. Periasamy and NHLBI Grants HL-63744, HL-65608, and HL-38324 to J. L. Zweier. Y. Zhou is a recipient of an American Heart Association (Ohio Valley) Postdoctoral Fellowship grant.

	ACKNOWLEDGMENTS

 
We thank M. Bonar for critical reading of the manuscript.

	FOOTNOTES

 

Address for reprint requests and other correspondence: M. Periasamy, Dept. of Physiology and Cell Biology, The Ohio State Univ. College of Medicine, 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210 (E-mail: periasamy.1{at}osu.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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