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Am J Physiol Heart Circ Physiol 293: H514-H519, 2007. First published March 23, 2007; doi:10.1152/ajpheart.00626.2006
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Blockade of both {alpha}1A- and {alpha}1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Chihiro Hosoda,1,2,* Masami Hiroyama,1,* Atsushi Sanbe,1 Jun-ichi Birumachi,1 Tadaichi Kitamura,2 Susanna Cotecchia,3 Paul C. Simpson,4 Gozoh Tsujimoto,5 and Akito Tanoue1

1Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; 2Department of Urology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; 3Institut de Pharmacologie et Toxicologie, Universit de Lausanne, Lausanne, Switzerland; 4Cardiology Division, San Francisco Veterans Affairs Medical Center, and the Cardiovascular Research Institute and Department of Medicine, University of California San Francisco, San Francisco, California; and 5Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

Submitted 13 June 2006 ; accepted in final form 22 March 2007


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Attenuation of early restenosis after percutaneous coronary intervention (PCI) is important for the successful treatment of coronary artery disease. Some clinical studies have shown that hypertension is a risk factor for early restenosis after PCI. These findings suggest that {alpha}1-adrenergic receptors ({alpha}1-ARs) may facilitate restenosis after PCI because of {alpha}1-AR's remarkable contribution to the onset of hypertension. In this study, we examined the neointimal formation after vascular injury in the femoral artery of {alpha}1A-knockout ({alpha}1A-KO), {alpha}1B-KO, {alpha}1D-KO, {alpha}1A-/{alpha}1B-AR double-KO ({alpha}1AB-KO), and wild-type mice to investigate the functional role of each {alpha}1-AR subtype in neointimal formation, which is known to promote restenosis. Neointimal formation 4 wk after wire injury was significantly (P < 0.05) smaller in {alpha}1AB-KO mice than in any other group of mice, while blood pressures were not altered in any of the groups of mice after wire injury compared with those before it. These results suggest that lack of both {alpha}1A- and {alpha}1B-ARs could be necessary to inhibit neointimal formation in the mouse femoral artery.

{alpha}1-adrenergic receptor; vascular injury; smooth muscle cell; femoral artery of mouse; wire injury

SINCE THE INTRODUCTION OF catheter-based coronary revascularization for the treatment of coronary artery disease, the procedure, termed percutaneous coronary intervention (PCI), has been improved with the development of newer devices, and its indication has been expanded with excellent success rates (>97%) (5). In approximately 20% of these patients, however, recurrent ischemia due to restenosis of the dilated segment developed within 6 mo (5). Because endothelial denudation following PCI stimulates smooth muscle cells to form neointima, neointimal formation is considered to be one of the most important mechanisms contributing to restenosis (9, 12, 17). Therefore, the elucidation of the precise mechanism of neointimal formation is important for the treatment and prevention of coronary artery disease. To elucidate the mechanisms of neointimal formation, a wire injury model of the mouse femoral artery was developed (6, 19, 23, 28). Furthermore, the introduction of genetically engineered mice into the vascular injury model enabled us to examine the role of specific molecules in neointimal formation (21, 25, 32, 33, 40).

{alpha}1-Adrenergic receptors ({alpha}1A, {alpha}1B, and {alpha}1D-AR), which activate vascular smooth muscle contraction, leading to vasoconstriction and blood pressure regulation (7, 24, 34), are involved in the contraction of human coronary smooth muscle cells (31) and the decrease in coronary blood flow after PCI (13). Moreover, hypertension, to which the onset {alpha}1-AR markedly contributes (1, 8, 22, 38), is a risk factor for early restenosis after PCI (2, 29). These findings suggest that {alpha}1-AR may be involved in restenosis after PCI. In fact, {alpha}1-AR-mediated norepinephrine stimulation induces neointimal formation (12). In addition, recent studies using rat vessels with {alpha}1-antagonists revealed that the {alpha}1A-AR subtype, but not the {alpha}1D-AR subtype, was certainly involved in catecholamine-stimulated neointimal formation (10, 12). However, the exact functional role of {alpha}1B-AR subtypes in neointimal formation remained unclear (10, 36) because of the lack of appropriate {alpha}1B-selective antagonists and satisfactory methods of quantitative {alpha}1-AR-subtype mRNA expression analysis.

Therefore, in this study, we examine the mRNA expression of each {alpha}1-AR subtype in the mouse femoral artery using an RT-PCR assay and further investigate the functional role of each {alpha}1-AR subtype in neointimal formation using a vascular injury model of mouse femoral artery in mice lacking the {alpha}1-AR subtype gene.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Mice lacking {alpha}1-AR subtypes. {alpha}1A-/{alpha}1B-AR double-knockout ({alpha}1AB-KO, {alpha}1AB–/–, {alpha}1A–/–/{alpha}1B–/–) mice, whose genetic background was C57Bl6/J (20), were bred with 129Sv mice to produce F1 heterozygous ({alpha}1A+/–/{alpha}1B+/–) mice, whose genetic background was a mixture of 129Sv mice and C57Bl6/J mice. For this study, wild-type (WT) mice, which were produced as {alpha}1A-/{alpha}1B-AR positive mice during {alpha}1AB-KO mice generation, were used as controls and maintained on the genetic background of 129Sv mice and C57BL/6 mice. F1 mice were subsequently intercrossed to generate {alpha}1AB-KO and {alpha}1A-KO ({alpha}1A–/–) mice. {alpha}1B-KO ({alpha}1B–/–) and {alpha}1D-KO ({alpha}1D–/–) mice had already been generated and their viability confirmed (7, 34). The genetic background of both {alpha}1B-KO mice and {alpha}1D-KO mice was the same (a mixture of 129Sv and C57Bl6/J). Thus the genetic background of WT, {alpha}1A-KO, {alpha}1B-KO, {alpha}1D-KO, and {alpha}1AB-KO mice was also the same. The genotypes of each {alpha}1-AR subtype were determined with DNA isolated from the mouse tails (7, 24, 34). Six groups of 16- to 24-wk-old male WT, {alpha}1A-KO, {alpha}1B-KO, {alpha}1D-KO, and {alpha}1AB-KO mice weighing between 25 and 35 g were used in this study. All mice were housed in animal quarters with a 12:12-h light-dark cycle and provided food and distilled water ad libitum. For all surgical procedures, the mice were anesthetized by intraperitoneal injection of 50 mg/kg Nembutal (Abbott Laboratories, North Chicago, IL) diluted in a 0.9% sodium chloride solution. All experiments were conducted in accordance with the guidelines for the care and use of animals approved by the ethics committee of the National Research Institute for Child Health and Development.

RNA isolation and RT-PCR. The femoral artery was isolated and dissected free of excess fat and connective tissue. These materials were then immediately pooled in the RNAlater RNA stabilization solution (Ambion, Austin, TX) for 1 day at room temperature so that the RNA volume would remain as large as possible. After that, the total RNA was extracted using ISOGEN (Nippon Gene, Tokyo, Japan) from each sample. The total RNA (<5 µg) was treated with RNase-free DNase (Takara Shuzo, Tokyo, Japan) and reverse-transcribed using random hexamers (34). One-tenth of each cDNA sample was amplified by PCR with a receptor-specific primer set and a primer set specific for GAPDH (27). Each sample contained the upstream and downstream primers (10 pmol of each), 0.25 mM of each dNTP, 50 mM KCl, 10 mM Tris·HCl, pH 8.6, 1.5 mM MgCl2, and 2.5 units of Taq DNA polymerase (Takara Shuzo).

The amplification reactions were conducted with a PCR thermal cycler (TaKaRa, Tokyo, Japan) at 95°C for 30 s, 65°C for 30 sec, and 72°C for 1 min for 25 cycles using specific primer sets: GAPDH, 5'-GGTCATCATCTCCGCCCCTTC-3' and 5'-CCACCACCCTGTTGCTGTAG-3'; {alpha}1A receptor, 5'-TACGTGCCACTGACCATCAT-3' and 5'-GCTTGGAAGACTGCCTTCTG-3'; {alpha}1B receptor, 5'-AACCTTGGGCATTGTAGTCG-3' and 5'-TGCCACTGTCATCCAGAGAG-3'; and {alpha}1D receptor, 5'-CGCTGTGGTGGGAACCGGCAG-3' and 5'-AGTTGGTGACCGTCTGCAAGT-3'. The products were detected under UV illumination after agarose gel electrophoresis.

Mouse femoral wire injury model. Surgery was carried out using a dissecting microscope (C-DSS 115, Nikon, Tokyo, Japan). Transluminal mechanical injury of the femoral arteries via arteriotomy in a small muscular branch using a straight spring wire (0.38 mm in diameter, no. C-SF-15-15, Cook, Bloomington, IN) was performed according to the method described previously (28). The wire was left in place for 1 min to denude and dilate the artery. The muscular branch was ligated, and the blood flow of the femoral artery was restored. One to five weeks later, the injured segment of the femoral artery was surgically exposed by intraperitoneal administration of an overdose of Nembutal. At death, the mice were perfused via the left ventricle with a 0.9% NaCl solution followed by perfusion fixation with 4% paraformaldehyde overnight at 4°C and embedded in paraffin. Uninjured femoral arteries were also used as controls.

Tail-cuff method. Systolic blood pressure was measured in conscious mice with a computerized tail-cuff system (Muromachi Kikai, Tokyo, Japan) that determines systolic blood pressure using a photoelectric sensor, as described previously (14). Before the study was initiated, at least 3 days of training (that is, sessions of unrecorded measurements) were provided for the mice to become accustomed to the tail-cuff procedure. Sessions of recorded measurements were then made from 1 to 5 PM daily on 3 consecutive days. Each session included more than 10 tail-cuff measurements; thus 30–50 measurements were used for the determination of the blood pressure of each mouse. For the inclusion of each set of measurements for an individual mouse, we required that the computer successfully identify the blood pressure in at least 7 of the 10 trials within the set.

Morphometry. Five serial sections (3 µm thick) from each artery were stained with elastica van Gieson staining to visualize the elastic laminae or with hematoxylin and eosin staining. The image was digitized using a digital camera (Axio-Cam HRC, Zeiss, Oberkochen, Germany) on a microscope (ECLIPSE TE300, Nikon, Tokyo, Japan). An image-processing and analysis program (NIH image, NIH, Bethesda, MD) was used to measure the total cross-sectional medial area (between the external elastic lamina and the internal elastic lamina) and the intimal area (between the innermost side of the arterial wall and the internal elastic lamina). Subsequently, the intimal area-to-medial area ratio was calculated.

Data analysis. Numerical results were expressed as the mean ± SE. One-way ANOVA followed by a Bonferroni post hoc test was used for pairwise multiple comparison. A P value of <0.05 was considered a significant difference.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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mRNA expression of {alpha}1-AR subtypes in the mouse femoral artery. RT-PCR was carried out to investigate the expression of each receptor in the femoral artery of KO mice as well as of the WT (control) mice. This assay revealed that the expression of each {alpha}1-AR subtype was detected in the femoral artery of the WT mouse (Fig. 1); that of {alpha}1A-AR was the most predominantly detected by the RT-PCR assay. This predominant expression pattern of {alpha}1A-AR in the mouse femoral artery was also observed by a quantitative analysis with a real-time PCR assay (data not shown), suggesting that {alpha}1A-AR was predominantly expressed among the {alpha}1-AR subtypes. This assay also revealed that the mRNA expressions of other types were increased in the KO mice. For instance, {alpha}1B-AR and {alpha}1D-AR were increased in {alpha}1A-KO mice, {alpha}1A-AR and {alpha}1D-AR were increased in {alpha}1B-KO mice, {alpha}1A-AR and {alpha}1B-AR were increased in {alpha}1D-KO mice, and {alpha}1D-AR was increased in {alpha}1AB-KO mice (Fig. 1).


Figure 1
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  		Fig. 1. mRNA expression of {alpha}1-adrenergic receptor (AR) subtypes in the femoral artery of wild-type (WT) mice. Total RNA was isolated from the femoral artery and then reverse transcribed. The expression levels of {alpha}1-AR subtypes were compared in all knockout (KO) mice by RT-PCR. In all types of mutant mice, the expression levels of other types of {alpha}1-AR were increased. GAPDH was used as a control. The presented result is representative of three separate experiments.

 
Blood pressure. The influence of surgery on the blood pressure was examined using the tail-cuff method. The blood pressure in each mutant mouse after surgery was not significantly different from that before the surgery (Table 1). With regard to the basal blood pressure, the blood pressure in {alpha}1D-KO mice was significantly lower than that in WT (Table 1). These results indicated that the surgical operation did not affect the blood pressure.


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  		Table 1. Comparison of the blood pressures before and after the surgical operation

 
Neointimal formation after vascular injury. The nonoperated normal femoral arteries of each group of mice were dissected and observed as controls. The gross and microscopic appearances of control femoral arteries in all groups of mice were similar and normal (Fig. 2D). We observed neointimal formation after wire injury of mouse femoral arteries. Quite consistently with a previous study (28), neointimal formation was observed in WT femoral arteries 1–5 wk after wire injury (data not shown). Neointimal formation, however, continued to grow for up to 4 wk after wire injury and did not advance further. Therefore, we subsequently examined the morphometric changes of the injured arteries 4 wk after denudation of the intima in each group of mice (Fig. 2, A–C, n = 10–12 mice/group). There was no significant difference in the medial area among all groups of mice (Fig. 2A, n = 10–12 mice/group). On the other hand, the neointimal area in {alpha}1AB-KO mice was significantly smaller than that in any other group of mice (P < 0.05) (Fig. 2B, n = 10–12 mice/group). Furthermore, the mean intimal area-to-medial area ratios in {alpha}1AB-KO mice were significantly smaller than those in any other group of mice (P < 0.05) (Fig. 2C, n = 10–12 mice/group). The neointimal area and mean intimal area-to-medial area ratios were 54 and 52% lower in {alpha}1AB-KO mice than in WT mice, respectively (Fig. 2, B and C). On the other hand, the neointimal area and mean intimal area-to-medial area ratios in other mice were not significantly different from those in WT mice (Fig. 2, A–C).


Figure 2
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  		Fig. 2. Morphometric analysis of injured mouse femoral arteries. The mean cross-sectional medial area (A), the mean cross-sectional intimal area (B), and the mean intimal area-to-medial area ratio (C) are shown. Values represent means ± SE of 10–12 independent experiments. *P < 0.05 vs. WT mice. D: representative cross sections of uninjured and 4 wk after wire injury of femoral arteries from WT and {alpha}1AB-KO mice with hematoxylin and eosin staining and elastica van Gieson staining. Neointimal formation after wire injury in {alpha}1A-KO, {alpha}1B-KO, and {alpha}1D-KO mice was similar to that in WT mice. Magnification x100.

 
A comparison of the expression levels of each {alpha}1-AR subtype between noninjured (control) and injured arteries. RT-PCR was carried out to determine which subtypes of {alpha}1-AR are expressed in the injured femoral artery. Interestingly, all types of {alpha}1-AR were increased in the injured femoral artery in WT, {alpha}1A-KO, {alpha}1B-KO, {alpha}1D-KO, and {alpha}1AB-KO mice (Fig. 3).


Figure 3
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  		Fig. 3. Comparison of {alpha}1-AR subtype expression between noninjured (control) artery and injured artery. The samples in the left and right lanes were taken control and after surgery, respectively. GAPDH was used as a control. The presented result is representative of three separate experiments.

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
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Since neointimal formation is considered to be one of the most important mechanisms that underlie restenosis (9, 12, 17), we analyzed the involvement of {alpha}1-AR in neointimal formation. For that purpose, we examined the mRNA expression level of each {alpha}1-AR subtype in the mouse femoral artery and investigated the functional role of those in neointimal formation 4 wk after wire injury in mice lacking the {alpha}1-AR subtype gene. An mRNA analysis of the {alpha}1-AR subtypes revealed that all subtypes of {alpha}1-AR were detected in mouse femoral arteries and that {alpha}1A-AR was most predominantly detected. Since mRNA abundance is not always reflected at the protein levels, we performed immunohistochemical studies using anti-mouse {alpha}1-AR antibodies to investigate the protein level of {alpha}1-AR in the femoral artery. No specific signal, however, was obtained by our immunohistochemical studies, probably due to insufficient specificity and/or sensitivity of the antibodies. In addition to the expression of the {alpha}1-AR subtypes in the femoral artery, the blood pressure was not altered after the wire injury. This indicated that the vascular injury model of the mouse femoral artery, with respect to {alpha}1-AR, was suitable to elucidate the mechanisms of neointimal formation. Both the neointimal area and the intimal area-to-medial area ratios in the femoral artery of {alpha}1AB-KO mice were significantly smaller than those in any other group of mice, while no difference was seen among {alpha}1A-KO, {alpha}1B-KO, {alpha}1D-KO, and WT mice. Other subtypes of {alpha}1-AR seemed to increase when one type of {alpha}1-AR expression was lost in the femoral artery. These results suggest that blockade of the signaling of both {alpha}1A-AR, which is predominant in the mouse femoral artery, and {alpha}1B-AR could be necessary to inhibit neointimal formation. Interestingly, the expression of all {alpha}1-AR types was increased in each mutant mouse after surgery, suggesting that those expressions were enhanced during intimal formation.

Regarding the functional role of {alpha}1-AR, recent studies have shown that all {alpha}1-AR subtypes in vascular smooth muscle cells mediate catecholamine-stimulated vasoconstriction (7, 15, 24, 34) and that {alpha}1-AR markedly contributes to the onset of hypertension (1, 8, 14, 22, 35, 38). Furthermore, other studies have revealed that the functional role of {alpha}1-ARs in the cardiovascular system is not only vasoconstriction but also postnatal cardiac development (20). In addition, previous studies using rat aorta, artery, and cultured cells with selective {alpha}1-antagonists have demonstrated that the activation of the {alpha}1-AR subtype (particularly, the {alpha}1A-AR subtype, but not the {alpha}1D-AR subtype) can induce neointimal formation (10, 12, 36), even though the {alpha}1B-AR and {alpha}1D-AR subtypes were mainly expressed in the rat aorta at both the mRNA and protein levels (11). On the other hand, the exact functional role of {alpha}1B-AR subtypes in neointimal formation still remains unclear because of lack of appropriate {alpha}1B-selective antagonists and satisfactory methods of quantitative {alpha}1-AR subtype mRNA expression analysis (10, 36, 41). As in a previous study using rat vessels (10, 12, 36), our study also showed that lack of the {alpha}1D-AR gene was not required to inhibit neointimal formation in the mouse femoral artery. The {alpha}1D-KO mice, however, cannot be directly compared with other {alpha}1-KO mice, because the blood pressure in {alpha}1D-KO mice was lower than that in other {alpha}1-KO mice. Regardless of low blood pressure, neointimal formation was normally observed in {alpha}1D-KO mice, emphasizing the fact that lack of the {alpha}1D-AR gene was not required to inhibit neointimal formation in the mouse femoral artery. Different from previous reports (10, 12, 36), on the other hand, our study showed that a single deletion of {alpha}1A-AR or {alpha}1B-AR subtype genes could not inhibit neointimal formation, but that deletion of both the {alpha}1A-AR and {alpha}1B-AR subtype genes could significantly inhibit it. These findings demonstrated that blockade of both {alpha}1A-AR and {alpha}1B-AR is required to inhibit neointimal formation.

With respect to the signaling pathway of {alpha}1-AR, previous studies have suggested that {alpha}1B-AR may control the receptor density and protein expression of {alpha}1A-AR by synergism and/or cross talk of the signaling pathways (16, 37). Although it is believed that all {alpha}1-AR subtypes are coupled to the Gq-protein (42), a study with {alpha}1AB-KO mice suggested the existence of distinct signaling pathways of extracellular signaling-regulated kinase via {alpha}1A-AR and of protein kinase C via {alpha}1B-AR in postnatal cardiac hypertrophy (20). In fact, these molecules differentially regulate the {alpha}1-AR-mediated contraction of smooth muscle cells in arteries (39). Similarly, in neointimal formation in the vascular injury model, these molecules were implicated in the signaling pathway (4, 30). However, the implication and synergism of these molecules in {alpha}1-AR-mediated neointimal formation remain uncertain. Similar signaling pathways and synergism may be implicated in neointimal formation.

On the other hand, there is no direct clinical evidence that the {alpha}1-AR antagonist has a preventive effect on restenosis after PCI. As described in the Introduction, however, recent clinical studies have suggested that {alpha}1-AR might facilitate restenosis after PCI (1, 2, 13, 22). In addition to these previous studies, the present study may support the importance of the proper blockade of {alpha}1A- and {alpha}1B-AR stimulation by the {alpha}1-AR antagonist for the prevention of restenosis. On the other hand, the large Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial recently conducted has raised a serious concern about the long-term use of {alpha}1-AR antagonists in the treatment of hypertension (3, 18). However, restenosis develops almost within 6 mo in patients who have undergone PCI (5). Therefore, the short-term use of {alpha}1-AR antagonists may be effective for the prevention of restenosis after PCI without adverse effects on cardiac function, especially in patients with complications of hypertension.

In summary, we characterized the mRNA expression of each {alpha}1-AR subtype and the functional role of those in neointimal formation in the mouse femoral artery. Our results demonstrated that this vascular injury model of the mouse femoral artery is suitable for the investigation of the functional role of {alpha}1-AR in neointimal formation after vascular injury. In addition, our findings suggested that both {alpha}1A-AR and {alpha}1B-AR subtypes were important for developing neointimal formation after vascular injury. Although this vascular injury model using genetically altered mice is not exactly the same as models with blocking receptors by antagonists, this result may support the clinical outcome that proper blockade of {alpha}1-AR stimulation by an {alpha}1-AR antagonist is needed for the prevention of restenosis after PCI without adverse effects on cardiac function, especially in patients with complications of hypertension. Further elucidation of the mechanisms underlying neointimal formation is to be expected.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
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REFERENCES
 
This work was supported in part by research grants from the Scientific Fund of the Ministry of Education, Science, and Culture of Japan; the Ministry of Human Health and Welfare of Japan; the Japan Health Sciences; the NOVARATIS Foundation; and the Takeda Science Foundation.


   ACKNOWLEDGMENTS
 
We are grateful to Masataka Sata (University of Tokyo) for the kind provision of a videotaped tutorial for the surgical procedure.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Tanoue, Dept. of Pharmacology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan (e-mail: atanoue{at}nch.go.jp)

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.

* C. Hosoda and M. Hiroyama contributed equally to this work. Back


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 DISCUSSION
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