(Stroke. 1997;28:1035-1042.)
© 1997 American Heart Association, Inc.
Articles |
Genetic Susceptibility to Experimental Cerebral Aneurysm Formation in the Rat
From the Institut National de la Santé et de la Recherche Médicale, INSERM U 367, Paris, France.
Correspondence to Michèle Coutard, INSERM U 460, CHU Xavier Bichat, 16 rue Henri Huchard BP 416, 75870-Paris Cedex 18, France.
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Abstract |
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Background and Purpose The susceptibility to experimental cerebral aneurysm formation in arteries of the circle of Willis was studied in four strains of rats presenting different susceptibilities to the spontaneous rupture of the internal elastic lamina in extracerebral arteries: Brown-Norway (BN)>Wistar>Long-Evans (LE)>LOU.
Methods Rats (150 g body weight) of the four strains were subjected to hypertension and a change in local cerebral blood flow by ligation of one common carotid artery for about 7 months. Six-month-old BN and LE rats were subjected to carotid ligation only for 11 to 13.5 months and treated or not (from 3 to 7 months of age) with an inhibitor of connective tissue fiber maturation, ß-aminopropionitrile (BAPN).
Results Aneurysmal structures (AS) occurred mainly in the anterior cerebral/anterior communicating arterial complex and proximal part of the posterior artery. In hypertensive rats, the AS incidence was LE, 56%; Wistar, 33%; BN, 17%; and LOU, 11%. When normotensive and subjected to carotid ligation only, LE rats showed an even greater susceptibility to AS formation (86%) than BN (7%). BAPN treatment did not influence AS formation: LE (60%) versus BN (8%).
Conclusions These results suggest that genetic factors are involved in cerebral aneurysm formation in the rat. The susceptibility of the internal elastic lamina of extracerebral arteries to spontaneous rupture does not appear to be a determinant genetic trait in the propensity to develop aneurysms in arteries of the circle of Willis. The comparison of these different rat strains may be very useful for studying factors contributing to cerebral aneurysm pathogenesis.
Key Words: cerebral aneurysm • genetics • rats
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Introduction |
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Although the etiology of cerebral aneurysms is still not established, aneurysms appear to result from the interplay between hemodynamics and structural properties of the arterial wall.1 A degenerative process in the arterial wall consecutive to the fatigue imposed by hemodynamic forces has been proposed as determinant.2 3 4 Medial gaps, which represent areas lacking medial smooth muscle cells, have been proposed by some5 6 7 as localizing factors in aneurysm formation, although this is still controversial.2 8 The earliest features observed in susceptible areas of experimental aneurysm development are damage to endothelial cells followed by alterations in the IEL and the media9 and changes in the medial elastic skeleton preceding morphological changes in the IEL.10 In a majority of reports concerning the etiology of cerebral aneurysms, the disintegration of the IEL was considered as an early key event.4 5 8 11 12
Intimal lesions characterized by the interruption of the IEL, with in some cases subsequent damage to endothelium and the underlying media, develop spontaneously with age in the caudal and renal arteries of the rat.13 14 Different susceptibilities to rupture of the IEL in the caudal artery between inbred rat strains have been established.15 BN rats are highly prone to IEL rupture because they develop large numbers of IEL interruptions in several arteries, particularly in the abdominal aorta.16 Recent observations on four strains of rats from sources different from those of the above studies have shown that BN rats are still the most susceptible to IEL rupture, the Wistar is intermediate, and the LE and LOU strains are the least, with the LE being slightly more susceptible than the LOU (M. Coutard, unpublished observations, 1994).
BAPN, which is a specific inhibitor of the enzyme lysyl oxidase17 involved in the cross-linking of elastic and collagen fibers,18 increases the incidence of experimental cerebral aneurysms in the rat.19 20 In addition, BAPN is able to increase the formation of arterial IEL interruptions21 and of aneurysmal-like structures in the testicular artery22 in the rat. Together these data suggest that the propensity to develop IEL interruptions may be determinant in cerebral aneurysm formation. We have thus investigated the incidence of experimental cerebral aneurysms in different rat strains with various susceptibilities to rupture of the IEL in extracerebral arteries (BN>Wistar>LE>LOU). First, we studied aneurysm formation in these four different rat strains with the previously described experimental model of cerebral aneurysm induction in the arteries of the circle of Willis in the rat,19 20 23 which associates experimental hypertension and ligation of one common carotid artery. By this procedure, hemodynamics were altered in two ways: an increase in intramural pressure and a modification of blood flow in some arteries that function as a shunt after carotid ligation.24 Although we did not measure blood flow within these arteries, it can be considered that an increase in local blood flow occurs,24 which may only be transient since arteries can adapt and local blood flow can return to normal values.
In this first experiment, we did not treat hypertensive rats with BAPN, since our purpose was to determine an eventual difference in aneurysm formation in rats pre-senting intrinsic differences in susceptibility to rupture of the IEL. Data from this first experiment showed that LE rats displayed the highest incidence of cerebral AS but also the highest level of blood pressure. Thus, to eliminate the possibility that these results might be due to the higher blood pressure levels in LE, we studied aneurysm formation in normotensive BN and LE rats subjected only to a modified local blood flow in cerebral arteries. It may be assumed that in these conditions aneurysm formation would be very low. Because, as reported above, the incidence of experimental cerebral aneurysms in rats is enhanced by BAPN treatment, in this second series of experiments we attempted to enhance aneurysm formation by treatment of half of these BN and LE rats with BAPN.
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Materials and Methods |
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Incidence of Cerebral Aneurysms in Different Strains of Experimental Hypertensive Rats
Animals
Inbred BN rats (n=20) and outbred Wistar rats (n=20) (Iffa-Credo, L'Arbresle, France), outbred LE rats (n=20) (CEJ, Le Genest Saint-Isle, France), and inbred LOU rats (n=28) (originally from CNRS and maintained in our laboratory) of about 150 g body weight were used.
The procedure for the care and euthanasia of studied animals was in accordance with European community standards on the care and use of laboratory animals.
Experimental Procedure
A clip of 0.2 mm in diameter was placed on the left renal
artery to activate the renin-angiotensin system and
consequently produce a sustained hypertension (two-kidney, one clip
Goldblatt model).25 One week later, the left common
carotid artery was ligated in two locations 5 mm apart and cut
between the two ligatures to avoid an eventual
revascularization. These two surgical procedures
were performed with rats under ether anesthesia. Rats were
fed normal laboratory chow and given tap water ad libitum.
Systolic blood pressure was recorded weekly by the indirect
tail-cuff transducer method (Narco Bio-systems). Several rats of each
strain did not show any increase in blood pressure several weeks after
renal artery clipping. Their blood pressure was then measured less
frequently, and these rats were thereafter considered as normotensive
and sham operated. Several rats died very soon postoperatively and were
autopsied when possible.
At about 7 months after carotid ligation, animals were anesthetized with pentobarbital (40 mg/kg; Nembutal, Abbot). A catheter was inserted into the aorta toward the heart just above the renal arteries. Procaine 1% (2 mL) was injected through the vena cava to induce cardiac arrest. The vena cava was cut for outflow of perfusates. About 2 mL of NaCl 0.9% and 10 mL of fixative solution (3% buffered glutaraldehyde) were perfused, and the brain was removed from the skull. The brain was postfixed for several hours in glutaraldehyde solution and rinsed in 150 mmol/L cacodylate buffer overnight. Under a dissecting microscope, the ventral part of the brain was exposed, and the arteries of both the anterior and posterior parts of the brain were gently removed. These two arterial networks then were postfixed in 1% OsO4 for 2 hours and processed for routine electron microscopy. Just before embedding in epoxy resin, arteries were observed under a dissecting microscope to check for the presence of AS, which are more easily detectable when arteries have been previously slightly blackened with osmium. Arteries were cut with a razor blade into small pieces of about 5 mm in length and embedded in sequence as recorded on a diagram made of the arteries of the ventral surface of the brain. Semithin sections of about 1.5 µm in thickness were made of several AS (n=15). In addition, we performed detailed microscopic examination of sections from the bifurcation of the AA and OA of both sides from normotensive and hypertensive BN (n=6) and LE (n=7) rats. This bifurcation, on the side opposite to carotid ligation, has been reported to be one of the sites most susceptible to experimental cerebral aneurysm development in the rat.26
Incidence of Aneurysms in Normotensive BN and LE
Rats
In a second experiment, 32 BN and 32 LE rats aged 3 months were
given normal laboratory chow, and from 4 to 7 months of age, half of
them received the same diet supplemented with 0.12% BAPN (Janssen
Labs). All rats were maintained in the above-described conditions. At
about 6 months of age, the left common carotid artery was ligated with
rats under ether anesthesia. Several rats died (8 LE and 14
BN) from different causes unrelated to the aim of the experiment and
were autopsied when possible.
Because we had no reference about cerebral aneurysm formation in these experimental conditions, first we killed 2 BN and 2 LE rats treated with BAPN 9 months after carotid ligation (at 15 months of age), then 3 BN and 2 LE BAPN-treated rats at 11 months after carotid ligation, and thereafter the remaining 7 BN and 5 LE BAPN-treated rats and the 9 BN and 9 LE untreated rats at 12.5 to 13.5 months after carotid ligation.
Arteries of the ventral part of the brain were processed as described above.
Statistical Analysis
To test the significance of differences between mean values from
the four strains of rats, one-way ANOVA was used, followed by Fisher's
test. For comparisons between only two groups of rats, Student's
t test was used.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Incidence of Cerebral Aneurysms in Different Strains of Experimental Hypertensive Rats
In the four strains, several rats died early (3 LE, 8 BN, 3 LOU, and 3 Wistar). In some of them (3 LE, 3 LOU, and 2 Wistar), the brains could not be examined. The brains that could be examined (8 BN, 1 Wistar) did not show AS, probably because the duration of the experiment was not sufficient for inducing them. However, half of these BN rats showed signs of hemorrhage in the cortex on the side contralateral to carotid ligation (right side). Three BN clipped rats showed small, round hemorrhagic spots, and one showed two important areas of hemorrhage. Although the level of blood pressure rose very quickly in several rats (reaching about 240 mm Hg 2 weeks after the clip had been placed on the renal artery) and the majority of rats that died had elevated arterial pressure, the rat that displayed the greatest hemorrhagic signs did not have the most elevated blood pressure (about 185 mm Hg), at least at 15 days after clipping (first record of blood pressure). Only one Wistar rat could be autopsied and showed a hemorrhagic spot in its right cerebral cortex. In the two other rat strains, no brains were in observable condition.
In our hands, the induction of experimental renovascular hypertension by placement of a clip on one renal artery was not 100% reliable. A variable number of rats in each strain showed no or only a transient increase in their systolic blood pressure, probably due to displacement of the clip. Thus, we considered rats with a mean systolic blood pressure of <170 mm Hg during the experimental period as normotensive.
Fig 1
summarizes the incidence of cerebral AS and levels
of blood pressure in the four strains of both normotensive (<170
mm Hg) and hypertensive (
170 mm Hg) groups of clipped rats. In
normotensive rats, only one individual showed an AS in the LE, Wistar,
and BN strains, whereas in the LOU strain none occurred. In
hypertensive rats, LE showed the greatest incidence of AS, Wistar was
intermediate, and BN and LOU showed a low incidence. However, the mean
systolic blood pressure of LE was significantly higher than
those of the three other strains of rats. When comparing normotensive
and hypertensive groups of rats, hypertension increased the incidence
of AS in LE, Wistar, and LOU but not in the BN rats. However, it should
be recalled that 8 BN rats with elevated blood pressure died early
after clipping, and in the remaining BN rats the mean level of blood
pressure was not very high.
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.001,
**P
In this study, we found the sites of predilection for AS formation to
be the complex of the AA and ACoA (Fig 2a) and the
proximal segment of the PA (Fig 2b). Fig 2c illustrates the morphology
of one AA/ACoA complex showing arterial bends. At a
microscopic level, a small curved artery from an AA/ACoA complex showed
AS changes at the internal side of the bend (Fig 2d) very similar to
those observed in the convoluted rat testicular artery,7
where spontaneous aneurysmal changes mainly occur at the lesser
curvature (Fig 2e). The left (ligated side) PA was often elongated and
in numerous cases showed the presence of a loop compared with the PA of
the nonligated side. As discussed later, this peculiar morphology may
be of importance in the development of AS at these sites.
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The microscopic observation of a bilobed saccular aneurysm from
an LE rat showed in one lobe the presence of cellular and fibrous
components (Fig 3a) and the accumulation of plasma
infiltrates and of numerous leukocytes in the other lobe (Fig 3b). The
latter probably represents a more recent stage of
aneurysmal development.
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The great majority of the AS observed present less developed
aneurysmal features than saccular aneurysms,
representing microaneurysms and mild dilatations.
Fig 3c
shows the left PA from a hypertensive LE rat with a very thin
wall and areas of dilatation consisting of either a decreased number of
medial cells and lack of the IEL or of only endothelial
cells lying on thin adventitial tissue. No such structural changes
occurred in the PA of the nonligated side (Fig 3d).
In the first experiment, we did not observe macroscopic AS at the
bifurcation of the AA and OA on the side opposite to the carotid
ligation, a site previously described to be one of the sites of
predilection for cerebral aneurysm formation in the
rat.26 We thus further investigated this AA/OA bifurcation
at the microscopic level in the two strains of rats with the highest
(LE-clipped) and the lowest (BN-clipped) incidence of macroscopic AS.
In the majority of these sites on both sides, at the apex of the
bifurcation an intimal cushion was present, and under this
structure the IEL was either absent, duplicated, or fragmented. In a
great number of cases, sections showed the absence of the IEL over a
short length in the vicinity of the intimal cushion (Fig 4a). No obvious difference was observed between the two
strains of rats; only two "early aneurysmal lesions" with
the absence of an intact IEL and a slightly dilated, thin media were
observed in normotensive LE rats (Fig 4b), although as noted by Futami
et al,27 these structural features may be observed even in
normal bifurcations. No apparent saccular aneurysms, defined as
dilated areas with only endothelial cells and fibrous
adventitia, were observed at the AA/OA bifurcation of these rats when
studied at the microscopic level.
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Incidence of AS in Normotensive BN and LE Rats Treated or Not
With BAPN
The Table summarizes the number of rats showing
different AS in arteries of the anterior and posterior parts of the
circle of Willis in LE and BN rats treated or not with BAPN. The level
of blood pressure at the time of death in these normotensive rats was
slightly more elevated in LE than BN in controls and in BAPN-treated
rats (Table), although these differences were not statistically
significant (P>.2 for controls and P>.3 for
BAPN-treated rats).
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LE rats showed a much greater total incidence of AS than BN, whether treated with BAPN or not. In contrast to the first experiment, a difference in AS incidence between normotensive LE and BN rats could be seen, probably due to different experimental conditions from using older rats and a longer duration of carotid occlusion.
In our experimental conditions, BAPN did not increase the incidence of AS. It may be noticed that several BAPN-treated rats were killed earlier than untreated rats (see "Materials and Methods"). However, at this time, only 1 of 4 LE rats displayed an AS compared with 4 of 5 about 3 months later. Thus, BAPN did not accelerate aneurysmal formation in our experimental conditions.
In 1 BAPN-treated LE rat, a saccular microaneurysm (Fig 4c)
with a very thin wall occurred at the apex of a branching of the AA,
forming a buttonholelike structure (as shown in Fig 2c), and in the
same animal a preaneurysmal lesion with a decreased medial
thickness was observed at the AA/OA bifurcation (Fig 4d).
In the PA of BAPN-treated rats, AS often appear macroscopically as
white and opaque structures. At a microscopic level, more cell
proliferation and a thicker adventitial tissue could be observed (Fig 3e) compared with untreated rats (Fig 3a).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study clearly showed that the LE rat strain was more susceptible to the development of cerebral AS than the BN rat, while it is clearly less prone to spontaneous rupture of the IEL in extracerebral arteries.16 In addition, LE and LOU rats showed very different susceptibilities to AS formation, whereas they present similar susceptibilities to IEL rupture. This suggests that the propensity of the IEL from extracerebral arteries to spontaneously rupture is not a major genetic determinant of the susceptibility to cerebral aneurysmal formation and that other factors may be of higher contributing importance. However, this does not exclude that the IEL degradation locally in cerebral arteries may be a very important early step in cerebral aneurysm pathogenesis.
In contrast to the results of the present study, in which LE rats showed a higher susceptibility to cerebral AS than BN rats, we have previously reported in the testicular artery a higher incidence in BN compared with LE of spontaneous aneurysmal-like structures, characterized in part by the absence of the IEL.22 This suggests that the testicular artery behaves like other systemic arteries for rupture of the IEL. In contrast, the situation in the cerebral arteries appears to be very different because genetic susceptibility to IEL rupture in extracerebral arteries does not correlate with cerebral aneurysm formation. This discrepancy between data obtained at cerebral and testicular levels leads us to reconsider our previous suggestion, proposing on a morphological basis the testicular artery as an eventual model for studying cerebral aneurysm pathogenesis.
In our experimental conditions, the light microscopic study of the bifurcation of the AA/OA did not reveal the presence of morphological alterations related to aneurysmal or even preaneurysmal changes, whereas other authors using this model of experimental induction of cerebral aneurysms in rats have reported this arterial bifurcation to be one of the most susceptible sites for aneurysm development.26 However, we used LE and BN rats instead of Sprague-Dawley rats and the two-kidney one clip Goldblatt model instead of deoxycorticosterone acetate–salt or ischemic renal models of experimental hypertension. Both the rat strain and the level and the course of hypertension induced by the different models used may account for the differences observed. From our experiments, we can conclude that when only hemodynamic parameters are modified, the sites with the highest susceptibility for AS development are very small arteries with a peculiar configuration that have to sustain an increase, at least transiently, in blood flow.
The difference in the susceptibility to AS formation between strains of rats strongly suggests that genetic factors may be involved in the pathogenesis of cerebral aneurysms. Among them, the arterial configuration, which itself may influence hemodynamic parameters, may play a role. Although in humans anatomic variations in the circle of Willis are considered by some to be normal and no more prevalent in subjects with intracranial aneurysms, certain variations may be commonly found with aneurysms of the ACoA28 and in other sites.29 30 In the rat, the morphology of the circle of Willis is not very different between individuals apart from two areas, the AA/ACoA complex and the origin of the PAs,31 which are also the arteries where AS develop. The comparison of the PA of the ligated side, which at least transiently receives an increased blood flow after carotid ligation, with that of the nonligated side showed an increase in the arterial diameter and an elongation with the frequent presence of a loop in the former. The morphology of the AA/ACoA complex is different in each individual and is characterized by a very irregular course of the arteries that may present various branchings, curves, and loops. We have previously shown that in the highly convoluted testicular artery of the spontaneously hypertensive rat, AS, sharing numerous characteristics with experimental cerebral aneurysms in rats, developed spontaneously at the internal part of the curves, whereas in the straight spermatic artery, of which the testicular artery is the continuity, no structural changes occurred.7 We did not observe any consistent difference in arterial configuration of the AA/ACoA complex between the different rat strains but a great range of variety within each strain. In addition, only some rats within any one (even inbred) strain developed AS at both susceptible arterial sites.
In humans, the presence of several affected members in the same family32 33 34 35 and in identical twins36 and the presence of multiple aneurysms in the same individual also suggest the implication of genetic factors. However, the familial aggregation of intracranial aneurysms is low (ie, less than 2%37 to 6.7%38 ) and considered by some to concern a specific small subpopulation,37 while that of multiple aneurysms is more elevated (ie, about 20%33 ). Thus, as previously suggested, if inherited factors are causal, they probably are multiple and/or require other associated conditions to be symptomatic. This view is supported in the present study by the occurrence of AS within only some individuals in outbred but also in inbred strains of rats.
The involvement of defective components of the extracellular matrix,
mainly collagen,39 40 41 42 43 44 has been suggested in cerebral
aneurysm formation in humans but still remains
controversial.45 46 In the rat, the previously reported
increased incidence of experimental cerebral aneurysms in
BAPN-treated animals19 20 suggests that defective
connective tissue may favor aneurysm development. We recently
reported that the LE rat showed higher amounts of elastin and lower
amounts of collagen than the BN.47 In addition, a lower
level of tropoelastin mRNA in growing BN rats was observed in both
abdominal and thoracic aorta, suggesting an intrinsic decreased
synthesis of elastin in BN. No difference between the two strains was
observed in 
1-type I collagen mRNA in young and adult rats, although
at 6 weeks of age, 1-type III collagen mRNA was lower in the
abdominal segment in LE compared with BN. Thus, it appears that the
lower content of aortic collagen in LE rats is not related to a
generalized decrease in mRNA collagen transcripts. In our experimental
conditions, we did not observe any increase in the incidence of
cerebral AS between BN and LE rats treated with BAPN, which inhibits
the maturation of connective tissue fibers. However, the treatment was
given in adult rats when the bulk of elastin synthesis had already
occurred, thus probably affecting this protein very little. As for
collagen, the turnover is greater and continues in adult life, and its
synthesis was probably more affected by BAPN in our experiments. This
effect of BAPN on connective tissue even in adult rats is suggested by
the increased occurrence of cerebral aneurysms when BAPN is
given from 4 months of age in hypertensive rats.20 In our
experiment, BAPN was given to normotensive rats subjected to carotid
ligation only. It is possible that the increase in blood flow without
associated hypertension was not sufficient to induce additional
aneurysmal changes even on a structurally different artery. In
addition, the duration of BAPN treatment (4 months) may have been
insufficient. In one BAPN-treated LE rat, we observed a
preaneurysmal lesion at the AA/OA bifurcation and a
microaneurysm at another AA branching. We did not observe
structural changes in these areas in untreated rats, suggesting that
the use of BAPN may increase the susceptibility to aneurysmal
changes at the apex of these bifurcations.
As for the presence of hemorrhagic signs within the cortex of several hypertensive rats, mainly in BN and also in one Wistar rat, this confirms a previous observation that when rendered hypertensive, BN rats showed a particular cerebrovascular fragility.16
Results of the present study suggest a genetic predisposition to cerebral aneurysm formation in the rat. The comparison of various biological parameters in strains of rats with high and low susceptibilities to aneurysm formation may point to eventual mechanisms involved in the pathogenesis of cerebral aneurysms.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by INSERM. We thank Catherine Chollet for her excellent technical assistance.
Received December 2, 1996; revision received February 14, 1997; accepted February 28, 1997.
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