© 1999 American Heart Association, Inc.
Original Contribution |
Vascular Injury Causes Neointimal Formation in Angiotensin II Type 1a Receptor Knockout Mice
From Department of Cardiovascular Medicine (K.H., I.K., Y.Y.), University of Tokyo Graduate School of Medicine, Tokyo; Lead Generation Research Laboratories (T.S.), Tanabe Seiyaku Co, Ltd, Osaka; and Institute of Applied Biochemistry (K.M.), University of Tsukuba, Ibaraki, Japan.
Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.u-tokyo.ac.jp
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Abstract |
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Abstract—Many studies using small-animal models suggest that angiotensin II (Ang II) plays an important role in neointimal formation after vascular injury. In the present study, we examined whether Ang II type 1 receptor (AT1)-mediated Ang II signaling is indispensable for the development of injury-induced neointimal formation using AT1a knockout (KO) mice. Reverse transcriptase–polymerase chain reaction analysis revealed that AT1 mRNA was not detectable in both uninjured and injured carotid arteries of KO mice, whereas the AT1 gene was expressed in uninjured carotid arteries of wild-type (WT) mice. At 14 days after injury, AT1 mRNA levels were increased by 1.5-fold in injured arteries of WT mice. Although AT2 mRNA was not detectable in uninjured arteries, expression of AT2 gene was induced in both animal groups at 2 weeks after injury. Vascular injury induced neointimal formation in KO mice as well as in WT mice. There were no significant differences between WT and KO mice in the extent of histological findings such as increased cross-sectional areas of the neointima and the media, the number of proliferating smooth muscle cells, and the amount of collagen and fibronectin. Treatment with subpressor doses of Ang II after injury enhanced the growth of neointima in WT mice but not in KO mice. Moreover, treatment with the selective AT1 antagonist CV-11974 before injury significantly decreased the formation of neointima in only WT mice, whereas treatment with the selective AT2 antagonist PD-123319 before injury had no effects in both animal groups. These results suggest that AT1-mediated Ang II signaling is not essential for the development of neointimal formation, although it may modify it.
Key Words: angiotensin • angioplasty • stenosis • carotid artery
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Introduction |
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Vascular injury induces migration of smooth muscle cells (SMCs) from the media to the intima and subsequent proliferation of SMCs within the intima. These vascular responses are proposed to be critical processes of neointimal formation and induce narrowing of the vascular lumen, resulting in arteriosclerosis.1 2 3 Many studies have demonstrated that angiotensin-converting enzyme (ACE) inhibitors4 5 prevent neointimal formation in the injury model of small animals, whereas other agents that have blood pressure–lowering effects fail to prevent it.4 In injured arteries, mRNA and/or protein levels of ACE,6 7 angiotensinogen,8 renin,7 and mRNA and/or binding activity of angiotensin II (Ang II) receptors7 9 have been reported to be increased. In addition, it has been reported that Ang II infusion into rat after arterial injury induces proliferative response in SMCs in the neointima,10 suggesting that the renin-angiotensin system (RAS) plays an important role in neointimal formation. However, ACE inhibitors did not sufficiently inhibit neointimal formation after angioplasty in human trials11 12 as well as in swine13 14 and nonhuman primates.15 These results suggest that the RAS is not important for the neointimal formation of some species or that the pathway of Ang II production is different among animal species.
The effects of Ang II are exerted through specific 7-transmembrane Ang II receptors.16 17 At present, Ang II receptors are divided into 2 subtypes, AT1 and AT2, and AT1 is further subdivided into AT1a and AT1b.16 It is generally accepted that most of the well-known Ang II functions in the cardiovascular system are mediated through AT1.17 It has also been reported that the predominant Ang II receptor in SMCs is the AT1 subtype17 and that AT1 stimulation plays a major role in the development of neointimal formation in injured arteries.9 18 In contrast, AT2 expression is abundant during the fetal stage but is rapidly decreased soon after birth in most adult organs including the vessels.19 20 Interestingly, AT2 is reexpressed in pathological situations such as neointimal formation induced by vascular injury.20 21 There are reports suggesting that AT2 is also involved in injury-induced neointimal formation, because blockade of AT2 with a specific antagonist was effective in preventing neointimal formation after injury.21 22 However, Nakajima et al20 have reported that AT2 elicited growth inhibition of vascular SMCs in opposition to the effects of AT1. Thus, the relative importance of Ang II receptor subtypes in the neointimal formation is still controversial.
We and others have recently generated AT1a knockout (KO) mice by gene targeting.23 24 In the present study, we report on an injury model of murine carotid artery by which we can obtain reproducible and circumferential intimal response and on the pathophysiological roles of the RAS in the injury-induced neointimal formation using AT1a KO mice. AT1 mRNA levels were increased in only injured arteries of wild-type (WT) mice, whereas expression of AT2 mRNA was induced by injury in both kinds of mice. Vascular injury induced neointimal formation in KO mice as well as WT mice. Prolonged Ang II treatment after injury enhanced neointimal formation in only WT mice. In this model, a selective AT1 antagonist significantly inhibited neointimal formation in only WT mice, whereas a selective AT2 antagonist did not inhibit it in both kinds of mice. These results suggest that although Ang II could modify neointimal formation through AT1, vascular injury can induce neointimal formation without the AT1-mediated Ang II signaling pathways.
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Materials and Methods |
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Neointimal Formation of Murine Carotid Arteries
All protocols were approved by local institutional guidelines for animal care of Tokyo University. AT1a KO mice (n=44) and WT mice (n=44) 18 to 22 weeks old from the same genetic background were used in the present study.23 Animals were housed under climate-controlled conditions with a 12-hour light/dark cycle and were provided standard food and water ad libitum. To reproducibly obtain neointimal formation, arterial injury was produced by modification of previously described methods under a dissecting microscope.25 In brief, mice were anesthetized with sodium pentobarbital (50 mg/kg IP). The curved flexible angioplasty wire (0.35-mm diameter) was introduced into the left common carotid artery via the external carotid artery and was passed along the vessel 3 times. Subsequently, a polyethylene tube (PE10) was immediately introduced into artery and passed along the vessel 3 times. The ratio of the polyethylene tube to artery was
1.2±0.09. The tube was then removed, and the external
carotid artery was tied off proximal to the incision hole with the
proximal ligature. All these procedures were performed within 10
minutes. There were no operative deaths in both kinds of animals. The
identical injury procedure was performed for each animal to obtain
reproducibly the same injury. All injured vessels showed a
circumferential (360°) intimal response. The right carotid artery was
sham-operated and used as a control. The segments of injured and
uninjured carotid artery were excised at 7 (n=5) and 14 days (n=5)
after vascular injury. Reverse transcriptase–polymerase chain reaction
(RT-PCR) analysis was performed using mRNA prepared from 4
different pools of arterial segments for each group.
RT-PCR Analysis
Total RNA was prepared from the murine carotid artery using RNA
STAT-60 (TEL-TEST, Inc) followed by digestion with DNase. We first
performed conventional RT-PCR analysis to detect whether Ang II
receptor genes are expressed in arteries. The competitive RT-PCR
analysis was also performed to quantify
AT1 and AT2 mRNA using the
deletion-mutated cRNA as described previously.26 27 28 The
amplification efficiencies of target and competitor transcripts are
equal under optimal concentrations of competitor transcripts. Because
the primers used for the amplification of AT1
correspond to common sequences between AT1a and
AT1b, both AT1a and
AT1b mRNA were amplified.27 28 To
verify that equal amounts of RNA were subjected to RT-PCR, GAPDH mRNA
was also amplified with the specific primers.27 28
Denaturing (94°C for 45 seconds), annealing (58°C for 1 minute),
and extension (72°C for 1 minute) reactions were performed for 30
cycles. To examine the activation of the RAS in this injury model, we
also quantified ACE mRNA levels using basically the same method as
described previously.28 Expression levels of ACE mRNA were
increased by 2.4-fold in this model of WT carotid arteries at 14 days
after injury (data not shown). The range of concentrations of sample
RNA and internal control–deleted cRNA, as well as the number of
amplification cycles, was selected from within the exponential
phase.
Histological Studies
At 2 weeks after injury, carotid arteries were fixed by
perfusion of 10% formalin under physiological
pressure. Fixed tissues were embedded in paraffin, sectioned at 4
µm thickness, and stained with hematoxylin-eosin (H&E) for overall
morphology or by the van Gieson method for collagen.
Immunohistochemical stainings for 
-smooth muscle actin,
proliferating cell nuclear antigen (PCNA), and fibronectin were carried
out on paraffin sections by using anti-human -smooth muscle actin
with EPOS system (Dako, Inc), anti-human PCNA with EPOS system (Dako),
and anti-human fibronectin (Sigma Chemical Co) with LSAB kit (Dako),
respectively. 3,3'-Diaminobenzidine tetrahydrochloride was used as
chromogen, and the sections were counterstained with only hematoxylin.
Areas of intima and media were selected (4 fields randomly),
photographed, and determined with the image analysis software
as described previously.27 For quantification of SMC
proliferation after vascular injury, all PCNA-labeled cells were
counted separately in the intima and media of 4 subsequent cross
sections [The replication index: (PCNA-positive nuclei/total
nuclei)x100]. To determine the degree of extracellular matrix
accumulation, we selected 5 fields randomly and calculated the ratio of
van Gieson–stained or fibronectin immunoreactive area divided by total
neointima area as described previously.27
Chronic Administration of Subpressor Dose of Ang II
An osmotic minipump (model 2002, Alza Corp) was implanted
subcutaneously into mice after injury (n=3). Subpressor dose of Ang II
(100 ng · kg-1 ·
min-1)27 or saline alone was
administered for 2 weeks. To monitor the hemodynamic
effects of Ang II treatment at 2 weeks after implantation,
arterial blood pressure was directly measured in conscious
mice under unrestrained conditions as described
previously.27 After blood pressure was recorded,
carotid arteries were excised and subjected to further
analysis.
Chronic Administration of AT1 or AT2
Antagonists
Administration of AT1
antagonist (CV-11974; 1 mg ·
kg-1 · d-1, n=4),
AT2 antagonist (PD-123319; 3 mg
· kg-1 · d-1,
n=4), or saline alone (n=3) via an implanted osmotic minipump (model
2002) was started 60 minutes before injury and continued for the next 2
weeks. At 2 weeks after injury, carotid arteries were excised and
subjected to additional analysis.
Statistical Analyses
All results are expressed as mean±SEM. Multiple comparisons
between 3 or more groups were carried out by 2-way ANOVA and Fisher
exact test for post hoc analyses. Statistical significance was
accepted at a value of P<0.05.
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Results |
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RT-PCR Analysis of AT1 and AT2 mRNA in Murine Carotid Arteries
To examine whether AT1 and AT2 mRNA are expressed in carotid arteries, we first performed RT-PCR analysis. RT-PCR analysis using mRNA of carotid arteries revealed that AT1 gene was expressed in WT mice, whereas AT1 mRNA was not detectable in arteries of KO mice (Table
).
AT2 mRNA was not detectable in uninjured arteries
of both animal groups (Table). The findings in WT mice were in
good agreement with the previous study of rat carotid
arteries.19 Next, we quantified changes of the
AT1 and AT2 mRNA levels
after vascular injury by competitive RT-PCR analysis (Figure 1). In WT mice, AT1
mRNA levels were significantly higher in injured arteries than in
uninjured arteries (1.5-fold; P<0.05) (Figure 1A).
AT1 expression was also not detected in injured
arteries of KO mice. Expression levels of AT2
mRNA were increased in arteries of both mice by vascular injury, and
there was no significant difference in the amount of
AT2 mRNA levels between WT and KO arteries
(Figure 1B).
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AT1 and
Effects of Arterial Injury on Neointimal
Formation
At 2 weeks after operation, sham treatment did not induce intimal
thickening in mice of either group. Unexpectedly, vascular injury
induced neointimal formation not only in WT mice but also
in KO mice (Figure 2A), and there were no
significant differences in cross-sectional areas of
neointima or media between WT and KO mice (Figure 2B and 2C), indicating that vascular injury can induce
neointimal formation without the
AT1-mediated signaling. To determine the nature
of the cells present in the vessel wall at 2 weeks after injury, we
performed immunohistochemical analysis using an antibody
against -smooth muscle actin. Almost all cells in the
neointima showed immunoreactivity with the antibody against
-smooth muscle actin (data not shown). To determine the SMC
proliferation in injured arteries, immunohistochemical analysis
was performed with an antibody against PCNA in serial sections. The
percentage of replicating SMCs in the neointima as
demonstrated by the immunoreactivity for PCNA was markedly increased at
7 days after injury (WT, 61.2%; KO, 63.7%) and decreased at 14 days
after injury (WT, 25.7%; KO, 21.3%) (Figure 2D). There were no
significant differences in these changes between WT and KO mice (Figure 2D).
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Histological Analysis
To further characterize the composition of the intimal lesion, we
measured the amount of extracellular matrix (ECM) proteins such as
collagen and fibronectin by the van Gieson staining and
immunohistochemistry using specific antibody, respectively. Expression
of fibronectin has been reported to be induced by Ang
II.18 The deposition of collagen and fibronectin was
detected in the neointima after injury in KO as well as WT
mice (Figure 3A). There were no
statistically significant differences in the area of these ECM
productions between KO and WT mice (Figure 3B).
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Effects of Ang II Treatment on Neointimal Formation
In the present study, the expression of the
AT2 gene was induced by arterial
injury in both kinds of mice (Table
and Figure 1B). It
has been reported that AT2 is involved in
neointimal formation after vascular
injury.21 22 To examine this possibility, we continuously
administered subpressor doses of Ang II into mice for 2 weeks
immediately after injury. Prolonged treatment with Ang II had no
effects on blood pressure or heart rate (data not shown). The Ang II
treatment enhanced the growth of neointima in only WT mice
but not in KO mice (Figure 4). The
results obtained in WT mice suggest that AT1
stimulation can enhance injury-induced neointimal
formation, and KO mice results suggest that AT2
is not involved in injury-induced neointimal formation.
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Effects of Treatment with AT1 or AT2
Antagonists on Neointimal Formation
Finally, we administered the AT1
antagonist CV-11974 or the AT2
antagonist PD-123319 into mice from 60 minutes before the
injury through the 2 weeks that followed. With some minor variation,
prolonged treatment with CV-11974 significantly inhibited (78±7%
inhibition; P<0.01) neointimal formation in
only WT mice (Figures 5 and 6c). This result is consistent
with the previous observation in the carotid injury model of
rat.18 CV-11974 had no effects on
neointima formation in KO mice (Figures 5 and 6e). Prolonged treatment with PD-123319 had no
inhibitory effects on injury-induced neointimal
formation in both kinds of mice (Figures 5, 6d, and 6f),
suggesting that AT2 is not involved in
injury-induced neointimal formation.
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Discussion |
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Genetically altered mice have considerable advantages to address the role of specific molecules. In the present study, we examined the specific role of Ang II in injury-induced neointimal formation using genetically AT1a-deleted mice. Unexpectedly, vascular injury induced neointimal formation and the deposition of collagen and fibronectin in AT1a KO mice as well as WT mice. AT1 mRNA levels were increased by 1.5-fold in only WT mice but not in KO mice. The expression of the AT2 gene in the artery was induced by vascular injury in both kinds of animals. Administration of Ang II immediately after injury enhanced neointimal formation in only WT mice. An AT1 antagonist, not an AT2 antagonist, inhibited neointimal formation in WT mice, whereas both antagonists had no inhibitory effects in KO mice. These results suggest that vascular injury can induce neointimal formation in the mice that genetically lack AT1-mediated Ang II signaling pathways, although Ang II plays an important role in neointimal formation through AT1 but not AT2.
Many animal models of injury-induced neointimal formation have been reported. Although Lindner et al25 developed the injury model of the murine carotid artery, which closely resembles that of the rat, this model induces only a negligible intimal response and has not been widely used. We established a new vascular injury model by which we can reproducibly induce circumferential neointimal lesions. We passed a polyethylene tube along the vessel, following their original procedures. In our model, formation of the neointima can be induced rapidly and measured reliably.
It has been reported that all components of the RAS were found in the vessel wall and the neointima6 7 8 9 29 and that although ACE inhibitors or AT1 antagonists effectively inhibited neointimal formation in rat models,4 5 18 ACE inhibitors were insufficient to reduce restenosis in human trials,11 12 as well as in porcine and nonhuman primate models.13 14 15 It has been reported that enzymes other than ACE can generate Ang II from Ang I30 and that protein levels of ACE in the neointima were not different from that in the media of the uninjured aorta,9 suggesting that Ang II generation through ACE-independent pathways may participate in neointimal formation. However, more recent studies using a porcine coronary artery model of vascular restenosis have demonstrated that chronic blockade of Ang II at the receptor level was also insufficient to inhibit intimal hyperplasia after injury,14 suggesting that the importance of Ang II for neointimal formation is dependent on animal models and that Ang II is not a major mediator of intimal thickening, at least in larger animals including humans.
To determine whether Ang II is indispensable for injury-induced neointimal formation in rodents, we examined genetically AT1-deleted mice. At 14 days after injury, almost the same degree of the neointimal lesion was observed in both KO and WT mice. Neointimal formation in KO mice was associated with the accumulation of SMCs, collagen, and fibronectin in the neointima, and all these changes were indistinguishable between WT and KO mice. These results suggest at least 2 possibilities. One is that Ang II is not involved in injury-induced neointimal formation in mice. Another possibility is that there are at least 2 different pathways, AT1-dependent and AT1-independent pathways, in injury-induced neointimal formation, and that although AT1 plays a pivotal role in injury-induced neointimal formation, the AT1-independent pathway substitutes fully for the AT1-dependent pathway in KO mice. Pharmacological studies using Ang II and an AT1 antagonist suggest that the latter possibility may be correct. Because infusion of Ang II enhanced and treatment with an AT1 antagonist inhibited the neointimal formation after the arterial injury in WT mice, Ang II may play a critical role in injury-induced neointimal formation through AT1. It is unknown at present how injury induced neointimal formation in KO mice in which AT1-evoked signalings are completely deleted. It has been reported that besides Ang II, many growth factors and vasoactive peptides such as platelet-derived growth factor, basic fibroblast growth factor, transforming growth factor-ß1, endothelin-1, and catecholamines are induced by injury and are implicated in the process of neointimal formation.1 2 31 32 33 34 35 36 37 These factors may influence the migration and proliferation of SMCs and production of ECM through similar signaling mechanisms.38 It remains to be determined what factors are activated by vascular injury in AT1a KO mice.
The role of AT2 in the neointimal formation has not yet been established. In the present study, the neointimal formation after vascular injury in carotid arteries was accompanied by an increase in levels of AT2 mRNA in KO mice as well as in WT mice. However, infusion of Ang II into KO mice that have only AT2 and treatment with AT2 antagonist of both mice had no effects on the ratio of neointima to media. These results suggest that at least in this model, AT2 is not involved in neointimal formation after vascular injury.
In summary, we demonstrated using a AT1a KO mice model that AT1-mediated Ang II signaling is not indispensable for the injury-induced neointimal formation and that signaling pathways other than those provoked by Ang II can fully induce responses to injury in the absence of AT1. The identification of the AT1-independent signaling pathways will provide new insights into the development of novel therapeutic strategies for preventing neointimal formation.
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Acknowledgments |
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This work was supported by a grant-in-aid for scientific research and developmental scientific research from the Ministry of Education, Science, and Culture and a grant from the Study Group of Molecular Cardiology Japan (Dr Komuro). We are very grateful to Drs Osamu Tojo, Kiyomichi Yoshimaru, and Masao Nishio (Osaka City University) for technical advice and encouragement, and we acknowledge Takeda Chemical Industries, Ltd (Osaka, Japan) for providing CV-11974.
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Footnotes |
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This manuscript was sent to Harry A. Fozzard, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received March 16, 1998; accepted October 21, 1998.
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