© 1999 American Heart Association, Inc.
Original Contributions |
Strain Differences in Neointimal Hyperplasia in the Rat
From the Departments of Surgery (S.A., A.L.N., T.P., G.J.C., T.H.W., M.K., D.C.A.), Physiology and Molecular Medicine (J.P.R., D.C.A.), and Pathology (W.T.G.), Medical College of Ohio, Toledo.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—We performed an initial screen of 11 rat strains by use of a standard balloon injury to the left iliac artery to observe whether genetically determined differences existed in the development of neointimal hyperplasia. Neointimal hyperplasia was assayed 8 weeks after the vascular injury on coded microscopic sections. Statistically significant differences in the percentages of the vascular wall cross-sectional areas composed of intima (percentage intima) secondary to neointimal hyperplasia were noted among the different rat strains (P<0.02), with the Brown-Norway (BN), Dark Agouti, and Milan normotensive strain rats having the highest and the spontaneously hypertensive rats (SHR) having the lowest percentages of intima. In a separate experiment, F1 hybrids of SHRxBN strains and parental BN and SHR underwent the vascular injury, and the parental strains again showed a statistically significant difference from one another in the mean percentage of intima (P<0.0001). The F1 hybrids showed an average percentage of intima intermediate between those of the parental strains. The average lumen size of the injured BN vessels were significantly smaller than that of the noninjured control vessels (P=0.044), but this significance disappeared when the circular areas of these vessels were calculated without taking neointimal growth into consideration (P=0.649). These results provide the groundwork for a genetic linkage analysis to identify the genes that influence the development of neointimal hyperplasia after vascular injury.
Key Words: neointimal hyperplasia • restenosis • rat, inbred strain • balloon injury
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Neointimal hyperplasia is a major cause of early restenosis after intervention in the cardiovascular system. For example, restenosis secondary to neointimal hyperplasia occurs in up to 50% of patients within 18 months after they undergo balloon angioplasty for coronary artery disease.1 Neointimal hyperplasia is also the cause of hemodynamically significant restenosis within 2 years at the endarterectomy site in
20% of patients who
undergo carotid endarterectomy. Also,
neointimal hyperplasia is a major cause of graft failure in
the coronary and peripheral arterial
systems.2 Neointimal hyperplasia is due to the response of the vasculature to injury and involves an initial vasospasm and the migration of smooth muscle cells (SMCs) from the media through the internal elastic lamina (IEL) to the injury site.3 4 5 These SMCs are stimulated to undergo simultaneous proliferative3 6 7 and apoptotic responses5 8 9 that lead to a relatively constant number of SMCs at the injury site in 2 weeks.6 7 Vascular occlusion can continue after 2 weeks without an additional increase in neointimal cell numbers1 6 because of increases in SMC size6 7 and the deposit of proteoglycan matrix in the neointima.1 3 10 11 12 Also, constriction of the vessel by collagen and elastin fibers, predominately in the media and adventitia, can contribute to restenosis.1 11 12 13
Many proteins, including transformation growth factor-ß, platelet-derived growth factor, nitric oxide synthetase, the renin-angiotensin cascade, and others, have been implicated in the genesis of this injury response.3 4 14 15 16 17 Each of the proteins involved in the response of the vasculature to injury is a potential candidate for allelic polymorphisms that may cause a genetic variation in the restenosis rates after vascular interventions for different patients and animal strains. Also, vascular fragility, which may determine the extent of damage that triggers the response of the vasculature to a given injury, may be similarly controlled by allelic variations in proteins involved in the synthesis of or composition of the elastin fiber network of the vessel wall.11 12 13 17 18 19 20
Relatively few studies have focused on possible genetic causes of neointimal hyperplasia and vascular restenosis after injury. However, a recent study has shown a probable genetic variation in human carotid artery wall thickness.21 Also, experimental studies have shown that the carotid arteries and thoracic aortas of spontaneously hypertensive rats (SHR) have an increased neointimal hyperplasia response 2 weeks after a standard injury when compared with Wistar-Kyoto and Sprague-Dawley (SD) rat vessels.22 23 Although these studies have shown that genetic elements may contribute to vascular restenosis, the preparative work for a formal genetic analysis to identify the genes responsible for these observed differences has not been performed.
The objective of this study was to screen inbred strains of rats for differences in neointimal hyperplasia development after a standard vascular injury. These strain differences presumably represent the effects of varying polygenic inheritance patterns among the different rat strains. Strain differences may also provide the basis for a total genome scan for linkage to neointimal hyperplasia in a segregating population that is derived from divergent rat strains.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Vascular Injury
Surgery was performed on male rats at 9 to 11 weeks of age that weighed 250 to 300 g. The rats were anesthetized with an intraperitoneal injection of ketamine and xylazine. Balloon catheter denudation of the endothelium of the left internal iliac artery was accomplished by a modification of the technique described by Baumgartner.24 The left femoral artery of the rats was exposed and dilated by the topical application of 1 drop of 1% lidocaine for 1 minute. A 2F balloon catheter was introduced into the femoral vessel and advanced into the distal aorta. The balloon was then inflated with 0.1 mL of normal saline and then retracted until the resistance of the left internal iliac artery was felt. The catheter was then partially deflated, if necessary, so that only a slight resistance was felt as it was withdrawn through the iliac artery. This process was repeated 3 times to ensure endothelial denudation. The balloon was not inflated in the sham-operated animals. The left femoral artery was ligated above and below the arteriotomy site, and the tissue layers and skin were approximated by standard surgical techniques. This animal study was approved by the Institutional Animal Care and Use Committee of the Medical College of Ohio and complied with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 86-23, revised 1985).
Morphology
Eight weeks after the vascular injury, the rats were
anesthetized and killed by a standard perfusion and fixation
technique with PBS at physiological pH and 10%
formalin at 100 mm Hg via cannulation of the left
ventricle.6 After 10 minutes of perfusion and fixation,
the entire distal aorta and common iliac arteries were retrieved. The
arteries were further fixed in 10% formalin for 1 week before
paraffin-embedding. Sections were obtained from the midportion of the
iliac arteries and stained with Verhoeff-van Gieson for
elastin.
Measurement of Vessel Areas
A Nikon camera/microscope at x10 magnification that was
attached to a Macintosh computer and a digital image processing and
analysis software program (National Institutes of Health Image
version 1.57b) were used to measure the total cross sectional area of
the midsegment of each artery on coded microscopic sections. The
arterial adventitia was excluded from the area
measurements. The intima was outlined and its area was measured. We
calculated the percentage of total arterial wall area due
to the intima (designated as the percentage of intima) by dividing the
intimal area by the total area of the artery. The lumens of the
sectioned vessels were sometimes partially collapsed. Therefore, to
calculate the circular vessel areas (CAs) outlined by the IEL, the
length of the IEL was measured in the mid segment of each vessel by
image analysis. CAs were calculated by the formula
CA=IEL2/4
. To correct for asymmetrical growth
of the neointimas, lumen size (LS) was calculated by
subtracting the neointimal area of each vessel from its CA:
LS=CA-Neointimal Area.
Statistical Analysis
Statistical analysis of intimal hyperplasia differences
among strains of rats included 1-way ANOVA that was followed in some
cases by specific contrasts and by the Duncan multiple range test with
the statistical package SPSS/PC+ (SPSS Inc). Differences were
considered significant at P<0.05.
Strain Screen
Ten inbred strains and 1 outbred strain of male rats were
surveyed. Strains that were surveyed included Lewis, Brown-Norway (BN),
spontaneously hypertensive rats (SHR), Albino surgery, Dahl
salt-sensitive rats (SS/Jr), Dahl salt-resistant rats (SR/Jr),
Wistar-Kyoto, Milan normotensive strain (MNS), Fischer 344,
Sprague-Dawley (SD), and Dark Agouti (DA). SR/Jr, SS/Jr, Albino
surgery, and MNS were from our colonies at the Medical College of Ohio.
The remainder were purchased from Harlan Sprague-Dawley, Inc
(Indianapolis, Ind). SD (Harlan Sprague Dawley) was the only outbred
strain surveyed. All rats were housed in our facility 1-week before
surgery.
SHRxBN Hybrid
On the basis of the results of the strain screen, 10 male BN
were bred to 10 female SHR that produced F1
(SHRxBN) hybrid rats. Seventeen male F1 hybrids
were weaned at 3 weeks of age, and, at 8 weeks of age, the 17
F1 hybrids, 15 male BN and 15 male SHR, underwent
the standard vascular injury. To assess neointimal
formation, area measurements and statistical analyses were
performed as outlined above except that 3 cross sections were obtained
from the proximal, middle, and distal segments of the surgically
injured vessels. After area measurements of the 3 sections were made on
coded sections, an average of the 3 measurements was calculated.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Strain Screen
Table 1
shows the
results of the strain comparisons. A total of 115 rats underwent
vascular injury, but 14 rats died after surgery. The total cross
sectional areas of the intima and the media of the left iliac arteries
differed significantly among the strains of rats (1-way ANOVA,
P=0.007) and ranged from 0.108
mm2 for DA to 0.206
mm2 for SS/Jr. The percentage of intima of the
left iliac artery after the vascular injury ranged from 15.1% in the
SHR strain to 38.3% in DA. The difference in the percentage of intima
of the arteries of all strains was significant at P=0.024 by
1-way ANOVA. The finding that the percentage of intima differed
significantly between the rat strains was important (Table 1)
because this ratio parameter corrects for variations in the
absolute area measurements in sections that are not perfectly
perpendicular to the vessel. The injury-stimulated intimal growth in
the responsive rat strains was often unevenly distributed around the
vessel lumens. Figure 1A and 1B are
photomicrographs of the left iliac arteries after vascular injury in BN
and SHR, respectively, in which the difference in intimal responses to
the standard vascular injury are apparent (Figure 1A and 1B). No
intimal hyperplasia was noted in the noninjured, contralateral right
common iliac arteries of both strains (Figure 1C and 1D). A
Duncan multiple range analysis with type I error set at
P=0.05 for comparison of the strains was performed. The DA,
BN, and MN strains showed significantly more neointimal
hyperplasia (ie, analysis of the percentage of intima) than did
the SHR (Table 1). Also, the DA showed significantly more
neointimal hyperplasia than the SD (Table 1).
|
|
Analysis of F1 Hybrids
Table 2 shows the
neointimal data for SHR and BN and their
F1 (SHRxBN) hybrids. Forty-seven rats underwent
surgery, and 8 rats (5 SHR, 2 F1, and 1 BN) died
from the procedure. There were no significant differences in the ages
and weights of these rats (data not shown) or in the total average
areas of the intima plus media of the injured left iliac arteries of
the parental and F1 rats (Table 2). The
areas of neointimal hyperplasia differed significantly
among the groups of animals, with the BN having a mean intimal area of
0.0820 mm2 and the SHR having a mean intimal
area of 0.0418 mm2 (ANOVA,
P=0.0018, Table 2). The average percentage of intima
of the left iliac arteries was 46.3%, 30.0%, and 19.9% for the BN,
F1 (SHRxBN), and the SHR, respectively (ANOVA,
P<0.0001; Table 2). A comparison of the
F1 value to the midparental value showed that the
mean percentage of intima of the F1 rats was not
statistically different (P=0.27) from the midpoint between
BN and SHR.
|
Figure 2 is a scattergraph of the
F1 neointima results. The range of
the percentage of intima of the left iliac artery measured for the BN
strain after the vascular injury was 35% to 57%. The SHR had the
lowest average percentage of intima of the left iliac artery (Table 2
) and a range of 10% to 45%, with the 45% value as an
outlier. The percentage of intima of the F1
hybrids ranged between 12% and 48%; a significant number of the
measurements of the F1 rats overlapped the
measurements of the SHR and BN (Figure 2).
|
Effects of Injury on CA and LS
The average CAs of the BN and SHR, which do not include
neointimal growth, were smaller in the sham-operated and
injured vessels when compared with the noninjured controls; however,
these differences were not significant (P>0.05, Table 3). The average LSs, which take
neointimal growth into account, were also smaller after
sham-operation or injury compared with the control vessels for these
strains, but these differences were only significant between the
injured and control BN vessels (P=0.044, Table 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Vascular occlusions after clinical intervention have been generally attributed as being due to neointimal hyperplasia, although it is apparent that restenosis is not always solely caused by the proliferation of SMCs at the injury site followed by the formation of neointima. Matrix formation,1 3 10 11 12 vasospasm,6 14 25 and constriction of the entire vessel by elastin and collagen fibers1 11 12 13 also play important roles in ultimate vessel patency. Variations in all of these biological processes between different patients or inbred animal strains may in part be due to genetic differences. A recent clinical study suggests that genetic factors contribute to carotid artery wall thickness, an independent risk factor for cardiovascular disease.21 Also, several studies have shown that different rat strains differ in vascular cell apoptosis,5 8 9 26 vascular wall fragility,18 the amount of elastase and lysyl oxidase in the elastin fiber networks of their vessel walls,19 and the amount of neointimal production after a standard vascular injury.22 23 Presumably, these strain differences are due to genetic factors.
To our knowledge, the current work is the first systematic study of representative rat strains to eventually allow a total genome scan to determine which genes are responsible for neointimal hyperplasia and was based on the following principles: Because all animals within an inbred rat strain are homozygous at essentially all genetic loci, the variance in neointimal hyperplasia and/or vessel wall constriction after vascular injury among different animals of the same strain must be attributable to environmental factors that cause somatic differences among individual animals; subtle variations in the surgical technique used to produce the vascular injury from animal to animal; or lack of precision in the measurement of neointimal hyperplasia. We have attempted to minimize these variables. First, all animals were provided with identical food and housing conditions. Second, the surgical procedure was standardized as much as possible, and the area measurements were made on coded sections. In the F1 study, the average percentage of intima was measured on multiple, coded sections taken throughout the injured artery in an effort to obtain a representative average area measurement. We operated only on male rats because of the reported inhibitory effects of estrogen and progesterone on smooth muscle proliferation and neointimal hyperplasia.27 28 Finally, an 8-week period before euthanasia was selected because this interval has been shown to maximize neointimal hyperplasia and minimize the effects of vasoconstriction in the calculation of arterial dimensions in rats.6
Even with the standardization of the surgical technique, 1 SHR in the
parental group of the F1 experiment had an
outlier value of 45% intima of its left iliac artery (Figure 2). This outlier value may have been due to a technical error
such as overinflation of the 2F balloon catheter. However, even with
this outlier, the mean percentage of intima of the left iliac artery in
the SHR strain was still lower than that in the BN strain (Table 2).
We initially performed a screen of 11 selected strains of rats to
determine whether they differed significantly in the amount of
neointima produced in response to a standardized vascular
injury. This led to the identification of several strains of rats with
a large amount of neointima production after injury
and other rat strains with significantly less neointima
production (Figure 1, Table 1). This variation of
the neointimal response to injury between SHR and BN
strains was confirmed in our second study (Figure 2, Table 2). Also, the injured BN vessels had a significant decrease in
their lumen areas compared with the noninjured control vessels,
although the decrease in LS after injury was not significant for the
SHR vessels (Table 3).
We chose the SHR and BN as parental strains for the
F1 study because of their lack of overlap in the
mean arterial percentage of intima after injury and the
maximum genetic polymorphism between these strains.29
Other major advantages of the SHR-BN pair are the existence of
recombinant inbred strains derived from SHR and BN and the existence of
a congenic SHR strain histocompatible with BN that allows transplants
between BN and SHR.30 The scattergraph of the
F1 hybrids shows that the mean percentage of
intima of the left iliac artery falls between the values for the
parental strains (Figure 2). In the F1
population, all animals are genetically heterozygous for each
parenteral chromosome including those carrying the information that
govern neointimal hyperplasia. The net effect of
F1 animals that inherit positive alleles from
a high-responder parent and negative alleles from a low-responder
parent would be (on average) a midparental value as observed (Table 2, Figure 2). This outcome is compatible with a polygenic
mechanism that results in varying levels of neointimal
hyperplasia after injury.
Recently, much speculation has occurred about the direct relationship
between hypertension and the development of neointimal
hyperplasia. Some animal studies have shown that antihypertensive
treatments, viz, with angiotensin-converting
inhibitors and 
1-adrenergic
antagonists decrease the development of intimal hyperplasia
after a vascular injury.3 25 Although the mechanism for
neointimal suppression is unknown in these studies, the
authors have alluded to the possible inhibition of vascular SMC
proliferation and protein matrix synthesis stimulated by
angiotensin II and noradrenaline. In our study,
we did not measure the blood pressures of the rats because of the
possible confounding effect of the added stress of blood pressure
determinations on intimal proliferation. However, the lowest amount of
neointimal hyperplasia was noted in the SHR, which are
chronically hypertensive when compared with the BN
strain.30 Thus, it is clear that any effect of
hypertension to exacerbate the cellular proliferative response of
intimal hyperplasia that we have observed (Figure 1) is
overridden by the genetic differences between SHR and BN that are
independent of blood pressure.
An intriguing possible explanation for the differences in neointimal proliferation observed between the BN and SHR strains is suggested by the results of recent in vitro studies by Orlov and colleagues8 26 that found a lower cell number and greater apoptosis in cell cultures derived from SHR aortas compared with cell cultures of BN aortas. Thus, it is possible that the lower amount of neointimal hyperplasia in the SHR than the BN is due to increased apoptosis in the SHR SMCs after the vascular injury. We are currently evaluating the possible differences in apoptosis in vivo between these rat strains to test this hypothesis.
There are several other possible explanations for the differences
observed between the neointima hyperplasia and the
constrictive vascular injury responses of the BN and SHR vessels.
Comparative studies have shown that BN may have more fragile vessels
than rats of the Long Evans (LE) strain.18 19
Specifically, BN arteries have significantly more spontaneous ruptures
of their IEL18 and increased elastase and decreased
lysyl oxidase activities in their vessel walls19 than LE
arteries. These differences in genetically determined vascular
fragility may also occur between the BN and SHR strains; it has been
shown recently in a combined renal transplantation and hypertensive
model that BN kidneys are more sensitive to glomerular
sclerosis and vascular proliferation lesions than SHR
kidneys.20 In addition, the sensitivity of the BN kidneys
to damage has a component that is independent of blood pressure. Thus,
although the 2F balloons were deflated until only a gentle pressure was
felt on withdrawal through the iliac arteries, it is possible that this
may have caused more damage to the fragile BN vessels, which, in turn,
elicited a more robust intimal hyperplasia response in the BN than the
SHR vessels (Figures 1 and 2, Tables 1 and 2). We are currently evaluating this possibility.
This study shows a significant difference in the development of neointimal hyperplasia among different inbred strains of rats. The discovery of strain differences is the initial step in a genetic analysis. Because the genetic differences that control the neointimal hyperplasia response between the SHR and BN strains seem to be codominant in F1 animals, the next step is to perform a genome scan for linkage of the neointimal hyperplasia phenotype in a segregating F2 population bred from the F1(SHRxBN) hybrids31 to allow identification of the genes responsible for neointimal hyperplasia.
Future applications of this approach may lead to the ultimate discovery of the genes responsible for the genetic variations in neointimal hyperplasia and other elements of the injury response of the vasculature that lead to restenosis. This possibility is supported by the finding that disease-specific quantitative trait loci identified in rodent genomic scans often have homologous quantitative trait loci found in similar regions of the human genome.31 32 Susceptibility to vascular restenosis is unlikely to be a simple mendelian trait because it is more multifactorial and polygenic in nature, as are many human disorders and diseases.31 32 Thus, patients with certain allelic combinations will be susceptible to this complication and patients with other alleles of the crucial genes will be resistant to restenosis. Because matrix formation,1 3 10 11 12 vasospasm,6 14 25 constriction of the vascular fibroelastic network,1 11 12 13 vascular apoptosis,5 8 9 26 vascular wall fragility,18 and other components of the vascular injury response are readily quantifiable in the rat vasculature, genome scans for the genes responsible for differences in these parameters among different inbred rat strains may allow for the eventual identification of the human genes that regulate these vascular responses.
|
Acknowledgments |
|---|
We acknowledge support from the Medical College of Ohio Foundation Cancer Biology Fund, the Medical College of Ohio Microscopy Imaging Center, and NIH grant HL-201716. Dr Rapp is the recipient of the Helen and Harold McMaster endowed chair in biochemistry and molecular biology. We thank Kay Langenderfer and Elisabeth Lanzl for help in the preparation of this manuscript.
|
Footnotes |
|---|
Reprint requests to David C. Allison, MD, PhD, Department of Surgery, 3035 Arlington Aven, Medical College of Ohio, Toledo, OH 44614-5804.
Received July 10, 1998; accepted March 12, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Lafont A, Guzman LA, Whitlow PL, Goormastic M, Cornhill JF, Chisolm GM. Restenosis after experimental angioplasty: intimal, medial, and adventitial changes associated with constrictive remodeling. Circ Res. 1995;76:996–1002.
2. Healy D, Zierler R, Nicholls S, Clowes A, Primozich J, Bergelin R, Strandness DJ. Long-term follow up and clinical outcome of carotid restenosis. J Vasc Surg. 1989;10:662–669.[Medline] [Order article via Infotrieve]
3. Powell JS, Muller RM, Baumgartner HR. Suppression of the vascular response to injury: the role of angiotensin converting enzyme inhibitors. J Am Coll Cardiol. 1991;17:137B–142B.
4.
Taubman MB, Rollins BJ, Poon M, Marmur J, Green RS,
Berk BC, Nadal-Ginard B. JE mRNA accumulates rapidly in aortic injury
and in platelet-derived growth factor-stimulated smooth muscle
cells. Circ Res. 1992;70:314–325.
5. Bochaton-Piallat ML, Gabbiani F, Redard M, Desmouliere A, Gabbiani G. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol. 1995;146:1059–1064.[Abstract]
6. Clowes AW, Reidy MA, Clowes MM. Mechanisms of stenosis after arterial injury. Lab Invest. 1983;49:208–215.[Medline] [Order article via Infotrieve]
7.
Liu MW, Roubin GS, King SB 3rd. Restenosis
after coronary angioplasty: potential biologic determinants and
role of intimal hyperplasia. Circulation. 1989;79:1374–1387.
8. Orlov SN, Dam TV, Tremblay J, Hamet P. Apoptosis in vascular smooth muscle cells: role of cell shrinkage. Biochem Biophys Res Commun. 1996;221:708–715.[Medline] [Order article via Infotrieve]
9. deBlois D, Tea BS, Dam TV, Tremblay J, Hamet P. Smooth muscle apoptosis during vascular regression in spontaneously hypertensive rats. Hypertension. 1997;29(pt 2):340–349.
10.
Bulkley BH, Hutchins GM. Accelerated
atherosclerosis: a morphologic study of 97 saphenous
vein coronary artery bypass grafts. Circulation. 1977;95:163–169.
11. Merrilees MJ, Tiang KM, Scott L. Changes in collagen fibril diameters across artery walls including a correlation with glycosaminoglycan content. Connect Tissue Res. 1987;16:237–257.[Medline] [Order article via Infotrieve]
12. Merrilees MJ, Beaumont B. Structural heterogeneity of the diffuse intimal thickening and correlation with distribution of TGF-ß1. J Vasc Res. 1993;30:293–302.[Medline] [Order article via Infotrieve]
13. Crissman RS, Guilford W. The three-dimensional architecture of the elastic-fiber network in canine hepatic portal system. Am J Anat. 1984;171:401–413.[Medline] [Order article via Infotrieve]
14.
Joly GA, Schini VB, Vanhoutte PM. Balloon injury and
interleukin-1 ß induce nitric oxide synthase activity in rat
carotid arteries. Circ Res. 1992;71:331–338.
15. Nikol S, Isner JM, Pickering JG, Kearney M, Weir L. Expression of transforming growth factor ß1 is increased in human vascular restenosis lesions. J Clin Invest. 1993;90:1582–1592.
16. Wolf YG, Rasmussen LM, Ruosiahti E. Antibodies against transforming growth factor-ß1 suppress intimal hyperplasia in a rat model. J Clin Invest. 1994;93:1172–1178.
17.
Nunes GL, Sgoutas DS, Redden RA, Sigman SR, Gravanis
MB, King SB, Berk BC. Combination of vitamins C and E alters the
response to coronary balloon injury in the pig.
Arterioscler Thromb Vasc Biol. 1995;15:156–165.
18. Capdeville M, Coutard M, Osborne-Pellegrin MJ. Spontaneous rupture of the internal elastic lamina in the rat: the manifestations of a genetically determined factor which may be linked to vascular fragility. Blood Vessels. 1989;26:197–212.[Medline] [Order article via Infotrieve]
19.
Osborne-Pellegrin MJ, Farjanel J, Hornebeck W. Role of
elastase and lysyl oxidase activity in spontaneous rupture of
internal elastic lamina in rats.
Arteriosclerosis. 1990;10:1136–1146.
20. Churchill PC, Churchill MC, Bidani AK, Griffin KA, Picken M, Pravenec M, Kren V, St Lezin E, Wang JM, Wang N, Kurtz TW. Genetic susceptibility to hypertension-induced renal damage in the rat: evidence based on kidney-specific genome transfer. J Clin Invest. 1997;100:1373–1382.[Medline] [Order article via Infotrieve]
21.
Duggirala R, Villalpando CG, O'Leary DH, Stern MP,
Blangero J. Genetic basis of variation in carotid wall thickness.
Stroke. 1996;27:833–837.
22. Kino H, Hama J, Takenaka T, Sugimura K, Shimada S, Yamamoto Y, Nagata S, Kai T, Horiuchi M, Katori R. Effect of an angiotensin II receptor antagonist, TCV-116, on neointimal formation following balloon injury in the SHR carotid artery. Clin Exp Pharmacol Physiol. 1995;1:S360–362.
23. Jandeleit-Dahm K, Burrell LM, Johnston CI, Koch KM. Elevated vascular angiotensin converting enzyme mediates increased neointima formation after balloon injury in spontaneously hypertensive rats. J Hypertens. 1997;15:643–650.[Medline] [Order article via Infotrieve]
24. Baumgartner HR, Studer A. Folgen des Gefasskatheterismus am normo- und hypercholesterinaemischen Kaninchen. Pathol Microbiol. 1966;29:393–405.
25.
Vachisht R, Sian M, Franks PJ, O'Malley MK. Long-term
reduction of intimal hyperplasia by the selective
1 adrenergic antagonist doxazosin.
Br J Surg. 1992;79:1285–1287.[Medline]
[Order article via Infotrieve]
26.
Hamet P, Richard L, Dam TV, Teiger E, Orlov SN, Gaboury
L, Gossard F, Tremblay J. Apoptosis in target organs of
hypertension. Hypertension. 1995;26:642–648.
27. Foegh ML, Asotra S, Howell MH, Ramwell PW. Estradiol inhibition of arterial neointimal hyperplasia after balloon injury. J Vasc Surg. 1994;19:722–726.[Medline] [Order article via Infotrieve]
28. Lee WS, Harder JA, Yoshizuma M, Lee ME, Haber E. Progesterone inhibits arterial smooth muscle cell proliferation. Nat Med. 1997;3:1005–1008.[Medline] [Order article via Infotrieve]
29. Jacob HJ, Brown DM, Bunker RK, Daly MJ, Dzau VJ, Goodman A, Koike G, Kren V, Kurtz T, Lernmark A. A genetic linkage map of the laboratory rat, Rattus norvegicus. Nat Genet. 1995;9:63–69.[Medline] [Order article via Infotrieve]
30. Pravenec M, Klir P, Kren V, Zicha J, Kunes J. An analysis of spontaneous hypertension in spontaneously hypertensive rats by means of new recombinant inbred strains. J Hypertens. 1989;7:217–222.[Medline] [Order article via Infotrieve]
31.
Rapp JP, Deng AY. Detection and positional cloning of
blood pressure quantitative trait loci: is it possible?
Hypertension. 1995;25:1121–1128.
32. Weeks DE, Lathrop GM. Polygenic disease: methods for mapping complex disease traits. Trends Genet. 1995;11:513–519.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  J. W. Gordon, C. Pagiatakis, J. Salma, M. Du, J. J. Andreucci, J. Zhao, G. Hou, R. L. Perry, Q. Dan, D. Courtman, et al. Protein Kinase A-regulated Assembly of a MEF2{middle dot}HDAC4 Repressor Complex Controls c-Jun Expression in Vascular Smooth Muscle Cells J. Biol. Chem., July 10, 2009; 284(28): 19027 - 19042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. H. Mnjoyan, D. Doan, J. L. Brandon, K. Felix, C. L. Sitter, A. A. Rege, T. A. Brock, and K. Fujise The critical role of the intrinsic VSMC proliferation and death programs in injury-induced neointimal hyperplasia Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2276 - H2284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Sheridan, M. J. Ferguson, M. R. Distasi, F. A. Witzmann, M. C. Dalsing, S. J. Miller, and J. L. Unthank Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 x Brown Norway hybrid rats Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3498 - H3505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Nestor, G. T. Cicila, S. E. Karol, K. M. Langenderfer, S. L. Hollopeter, and D. C. Allison Linkage analysis of neointimal hyperplasia and vascular wall transformation after balloon angioplasty Physiol Genomics, April 13, 2006; 25(2): 286 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Jones and K. Ravid Vascular Smooth Muscle Polyploidization as a Biomarker for Aging and Its Impact on Differential Gene Expression J. Biol. Chem., February 13, 2004; 279(7): 5306 - 5313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Forte, S. Esposito, M. De Feo, U. Galderisi, C. Quarto, F. Esposito, A. Renzulli, L. Berrino, M. Cipollaro, L. Agozzino, et al. Stenosis progression after surgical injury in Milan hypertensive rat carotid arteries Cardiovasc Res, December 1, 2003; 60(3): 654 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Kuhel, B. Zhu, D. P. Witte, and D. Y. Hui Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 955 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Zhu, D. G. Kuhel, D. P. Witte, and D. Y. Hui Apolipoprotein E Inhibits Neointimal Hyperplasia after Arterial Injury in Mice Am. J. Pathol., December 1, 2000; 157(6): 1839 - 1848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Coutard, W. Huang, M. Osborne-Pellegrin, and H. A. Kontos Heritability of Intracerebral Hemorrhagic Lesions and Cerebral Aneurysms in the Rat Editorial Comment Stroke, November 1, 2000; 31(11): 2678 - 2684. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||