(Stroke. 1995;26:1649-1654.)
© 1995 American Heart Association, Inc.
Articles |
Basic Fibroblast Growth Factor May Repair Experimental Cerebral Aneurysms in Rats
From the Department of Neurosurgery, Kanazawa University School of Medicine, Kanazawa, Japan.
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Abstract |
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Background and Purpose To determine whether basic fibroblast growth factor (FGF) can induce proliferative response of endothelial cells and/or smooth muscle cells in aneurysmal lesions, we investigated the effect of the intravenous administration of basic FGF on experimental cerebral aneurysms.
Methods Cerebral aneurysms were induced in rats by ligation of the unilateral common carotid artery, producing hypertension. Three months later, basic FGF was intravenously injected in two groups of randomly divided rats on days 1, 3, and 5 at two different doses (low dose: 2 µg/100 g body wt per day; high dose: 5 µg/100 g body wt per day). In a control group, normal saline was similarly injected. The junctions of the anterior cerebral artery (ACA) and the olfactory artery (OA) were examined with a light microscope. Aneurysmal changes were defined as the lesions with discontinuity of the internal elastic lamina in more than half of the outward dilated wall. Depending on whether the smooth muscle cell layer was present in the whole wall, the lesions were divided into two stages: early aneurysmal lesion (whole area) and saccular aneurysm (not totally preserved).
Results The control and the low-dose groups presented no obvious intimal thickening in the intact ACA-OA junctions of both nonligated and ligated sides as well as in the aneurysmal changes. In contrast, in the high-dose group, various degrees of intimal thickening in the wall were detected in 7 of 15 early aneurysmal lesions (P=.019, Fisher's exact test). Immunohistochemistry showed the proliferated cells to be smooth muscle cells.
Conclusions These results demonstrate that exogenous basic FGF induces the proliferative response of smooth muscle cells in aneurysmal lesions in rats.
Key Words: aneurysm • growth factors • muscle, smooth • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hashimoto et al1 produced saccular cerebral aneurysms in rats by ligating the unilateral common carotid artery and rendering the animals hypertensive with deoxycorticosterone and salt, aided by feeding the rats BAPN, which is a lathyrogen, to inhibit cross-linking of collagen and elastin. Since then, the cerebral aneurysm models using rats2 3 or monkeys4 5 have been established by his coworkers. In their studies, the junction of the ACA and the OA on the nonligated side, facing hemodynamic stress augmented by the experimental maneuver, is one of the sites most susceptible to aneurysm development.6 7 There is a morphological similarity between experimentally induced aneurysmal lesions and human cerebral aneurysms in autopsy materials. Moreover, the models permit the investigation of the early morphological changes in the cerebral arterial wall during the development of cerebral aneurysms. Previous studies showed the degeneration of endothelial cells, the disappearance of the internal elastic lamina, and thinning of the medial smooth muscle cells in early aneurysmal lesions.8 9 In these findings, the changes in the endothelium precede the others.3 5 6 This endothelial degeneration has been thought to occur as a result of vascular injury caused by hemodynamic stress.3 5 6 In general, vascular injury has been demonstrated to cause a proliferative response of smooth muscle cells, resulting in atherosclerosis or restenosis after angioplasty or endarterectomy.10 11 12 These observations suggest that certain mechanisms inhibiting the proliferative response may play a role in the development of cerebral aneurysms. Therefore, it is hypothesized that the wall of cerebral aneurysms may be repaired by facilitating cell proliferation.
Basic FGF is a pluripotent growth factor that is implicated in many aspects of the growth and differentiation of mesodermal and neuroectodermal cells.13 In vascular constituents, basic FGF is a well-known mitogen for endothelial cells14 and smooth muscle cells.13 15 16 17 It has been reported that the systemic administration of basic FGF enhances endothelial cell and smooth muscle cell proliferation in balloon-injured carotid artery models.15 18 In experimental cerebral aneurysms, the systemic administration of basic FGF may cause the proliferative response of endothelial cells and/or smooth muscle cells, resulting in the subsequent repair of cerebral aneurysmal wall.
In the present study, we induced experimental cerebral aneurysms in rats by the modified Hashimoto method,1 2 3 6 19 in which deoxycorticosterone and BAPN are not used because deoxycorticosterone may decrease the permeability of exogenous basic FGF through the endothelium into the arterial wall, and BAPN may affect the content of endogenous basic FGF in the extracellular matrix20 by causing the structural changes of extracellular matrix. Using the present animal model, we investigated the therapeutic effects of intravenously administered basic FGF on experimental cerebral aneurysms in rats.
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Materials and Methods |
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Animal Preparation
Cerebral aneurysms in rats were induced according to the modified Hashimoto method.1 2 3 6 19 After the intraperitoneal injection of chloral hydrate (3%, 0.01 mL/g body wt), 59 male Sprague-Dawley rats ranging from 6 to 7 weeks of age underwent ligation of the left common carotid artery and the posterior branches of both renal arteries. One week after the operation, 1% saline was substituted for drinking water. At 3 months, the rats were divided into the following three groups in random sequences. In group 1, 16 rats were given 2 µg/100 g body wt per day of basic FGF on days 1, 3, and 5 intravenously through the tail vein (low-dose group). Similarly, in group 2, 31 rats were injected with 5 µg/100 g body wt per day of basic FGF on three alternative days as described above (high-dose group). In group 3, 12 rats were similarly injected with normal saline as a control group on the same time schedule. Recombinant basic FGF generously supplied by Takeda Chemical Industries Ltd was used after dilution to a concentration of 20 µg/mL in distilled water. This basic FGF has a biological activity of 2 to 4 U/ng in a standard 3T3 DNA synthesis assay.21 One week after the final injection, the rats were killed. Blood pressure was measured twice by tail-cuff autopickup plethysmographic methods with rats in an unanesthetized state just before the aneurysm-induction procedure and just before death. The rats, under general anesthesia, were cannulated in the ascending aorta through the left cardiac ventricle and perfused at a pressure of 80 mm Hg with 4% paraformaldehyde in phosphate-buffered saline. After perfusion, the major arteries at the base of the brain were carefully dissected under a surgical microscope. The specimens were immersed in 4% paraformaldehyde in phosphate-buffered saline for 24 hours. After being dehydrated in graded alcohol, the specimens were embedded in paraffin, and 4-µm-thick sections were cut.
Light Microscopic Examination
Using elastica–van Gieson stain and a light microscope, we
examined the bifurcation of the ACA and the OA on both sides where the
nonligated side was reported to be the most preferential site of
experimental cerebral aneurysms in rats.6 7
Moreover, to distinguish between smooth muscle cells and
endothelial cells, we performed immunohistochemical
studies using mouse monoclonal antibody against 
-smooth muscle actin
(ZYMED Laboratories Inc) without dilution and rabbit monoclonal
antibody against human von Willebrand factor (DAKO, DK-2600) at
a dilution of 1/400. It was previously reported that the former
specifically reacts with -smooth muscle isoform of
actin,22 whereas the latter reacts with factor
VIII–related antigen of endothelial
cells.23 In both antibodies, the cross-reaction to each
antigen in rats was confirmed.24 25 After the inactivation
of intrinsic peroxidase with H2O2 in methanol
and blocking of nonspecific binding with normal horse serum at a
dilution of 1/50, the antibodies were applied to the serial sections
for 24 hours at 4°C. The sections were then incubated with
biotin-labeled horse IgG against mouse IgG at a dilution of 1/100 for 1
hour at 37°C, followed by the avidin-biotin procedure, and
counterstained with hematoxylin. Sections incubated with normal mouse
or rabbit serum served as negative controls.
Definitions and Judgments
The definition of aneurysmal changes and classification
of lesions were made by one of the authors (K.F.). Aneurysmal
changes were defined as the lesions showing outward dilatation of the
wall accompanied by the discontinuity of the internal elastic lamina in
more than half the length of the dilated wall. The lesions were
classified into two stages: (1) early aneurysmal lesion
preserving the smooth muscle cell layer in the whole area of the
dilated wall and (2) saccular aneurysm lacking the smooth
muscle cell layer even in a part of the whole area of the lesion. Using
the above definitions, all of the ACA-OA junctions were studied by two
of the authors (O.T. and S.K.), who had enough knowledge of the
histology of cerebral arteries in rats and who were blinded to the
treatments given the rats. The critical points were to determine
whether an aneurysmal change was present, whether an
aneurysmal change belonged to the early aneurysmal
lesions or the saccular aneurysms, and whether the
aneurysmal change presented proliferative change. A
decision was made only when the two reviewers reached the same
conclusion.
Statistical Analysis
The difference in blood pressure just before the
aneurysm-induction procedure and just before death among groups
1, 2, and 3 was estimated by Student's t test. Fisher's
exact test was used to compare the incidence of proliferative change
induced by basic FGF administration among the groups and between the
two stages of aneurysmal changes in each group. A value of
P<.05 on two-sided tests was considered to be statistically
significant.
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Results |
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In groups 1, 2, and 3, the maximum blood pressure was 123±13, 124±11, and 120±12 mm Hg just before surgery, respectively; it was 178±22, 180±25, and 178±21 mm Hg, respectively, just before death in each group. There was no significant difference among these three groups (P>.1, Student's t test).
ACA-OA Junction on the Nonligated Side
Control Group
In 7 of the 12 rats (58.3%) in this group, the aneurysmal
changes were detected (Table
). Four of the 7
aneurysmal changes were included in the early
aneurysmal lesions (Fig 1), which always existed
on the side of the ACA just distal to the apex of the ACA-OA junction.
Along the inner surface of the arterial wall, a monolayer
of endothelial cells was observed ("e" in Fig 1).
At the portion of the lesions nearest to the apex, there was a focal
protrusion of the intima that had been described as an intimal pad
always located near the apex on the distal side of the ACA ("in"
in Fig 1).26 The internal elastic lamina was continuous
along the curvature of the apex except for the wall of the lesions
("i" in Fig 1). At the orifice of the lesions, the internal
elastic lamina abruptly discontinued or tapered into the wall of the
lesions (arrows in Fig 1). In the wall of the lesions, residual
fragments of the internal elastic lamina were observed for variable
distances (arrowheads in Fig 1). Between the
endothelial cell layer and the traces of the internal
elastic lamina, there were no apparent cellular components except for
the intimal pad. In the lesions, medial smooth muscle cells ("s"
in Fig 2) were stretched and thinned in the various
degrees compared with the other portions of the artery but never
protruded toward the arterial lumen. In the outermost layer
of the artery, there were scattered fibroblasts and multilayered
fibrous connective tissue ("a" in Fig 2). The wall of the lesions
was dilated in various degrees toward the outside of the artery.
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In 3 of the 12 rats, saccular aneurysms developed. The wall of the lesions mainly composed of the endothelial cells and the fibrous adventitia prominently dilated outward. The internal elastic lamina was completely absent in the aneurysmal wall. The medial smooth muscle layer tapered and disappeared on the arterial wall adjacent to the aneurysmal orifice or, more often, on the aneurysmal wall.
Low-Dose Group
In 16 rats of group 1, early aneurysmal lesions were
detected in 7 and saccular aneurysms in 3. These
aneurysmal changes showed no marked morphological differences
compared with the lesions observed in the untreated group. As in the
untreated group, no cellular components were observed between the
endothelium and the fragmented, residual internal
elastic lamina. Accordingly, the proliferative response was not
confirmed in this group.
High-Dose Group
In 31 rats of group 2, 15 early aneurysmal lesions and 8
saccular aneurysms were observed. The incidence of early
aneurysmal lesions or saccular aneurysms showed no
significant difference compared with that in the other groups
(P>.1, Fisher's exact test). There were no
aneurysmal changes in the remaining 8 bifurcations. In 8
saccular aneurysms and 8 bifurcations with no
aneurysmal changes, there were no apparent intimal protrusions
indicative of proliferative cells (Fig 2
). On the other hand, 7 of the
15 early aneurysmal lesions showed various degrees of cell
proliferation on the luminal side of the residual and fragmented
internal elastic lamina (Fig 3A). The incidence of the
proliferative change in early aneurysmal lesions was
significantly higher in the high-dose group (P=.019,
Fisher's exact test) compared with that in the combined control and
low-dose groups.
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The original lumen of the aneurysmal changes could be
demarcated by the traces of the internal elastic lamina ("i" in
Fig 3A) or by the morphological difference of proliferative cells
("p" in Fig 3A). The cell arrangement of the proliferated cells
was apparently irregular compared with the surrounding smooth muscle
cells or endothelial cells. The proliferated cells had
round or oval nuclei with spindle-shaped cytoplasm. These intimal
proliferated cells existed as a tiny or thin protrusion consisting of
two or three layers of cells covering the inner surface of the wall of
the lesions. In this respect, they were apparently distinct from the
intimal pads forming the prominent protrusion existing within a
considerably short distance near the apex. However, in three early
aneurysmal lesions, the intimal proliferation was continuous
with the intimal pads. In one early aneurysmal lesion
accompanied by the most advanced intimal proliferation, proliferated
cells not only filled the original lumen of the lesion but also
protruded toward the vascular lumen and prominently extended distally
along the internal elastic lamina ("p" in Fig 4).
Outside the early aneurysmal lesions and saccular
aneurysms, no proliferative changes were detected.
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ACA-OA Junction on the Ligated Side
In all of the three groups, except for the usually observed
intimal pads, there were neither apparent aneurysmal changes
nor cellular components between endothelial cells and
the internal elastic lamina.
Immunohistochemistry of the Early Aneurysmal Lesions With
Intimal Proliferation
-Smooth muscle cell actin was immunohistochemically stained in
the proliferated intimal cells (arrows in Fig 3B) as well as medial
smooth muscle cells ("s" in Fig 3B) but not in
endothelial cells ("e" in Fig 3B) or in
adventitial fibroblasts ("a" in Fig 3B). On the other hand, von
Willebrand factor (arrowheads in Fig 3C) was stained in the
monolayer of the endothelial cells ("e" in Fig 3C) lining the inner surface of the arterial wall and of
the lesions with or without the intimal proliferation. In negative
controls, no immunochemical reactions were observed.
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Discussion |
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In the present study, we redefined the aneurysmal changes with special attention focused on the discontinuity of the internal elastic lamina. It is not only apparent in the elastica–van Gieson–stained specimens, it is one of the most essential factors for the aneurysm formation as well.8 9 27 28 29 30 As previously reported, the internal elastic lamina in the ACA-OA junctions in normal rats presents splitting and fragmentation under the intimal pad.7 26 Those junctions were excluded from our definition of aneurysmal changes. Kim et al5 7 studied sequential alterations in aneurysmal lesions of rats on the basis of the degree of depression and thinning of the arterial wall. They classified these lesions into four groups: (1) no depression, (2) shallow depression, (3) small evagination, and (4) apparent aneurysmal bulge. In our study, there are many variations in the degrees of depression and thinning, even in normal bifurcations (data not shown). Therefore, it is difficult to distinguish between intact arterial bifurcations and early aneurysmal lesions. Henceforth, we propose the new classification of the aneurysmal changes into two stages, depending on whether the smooth muscle layer is present in the whole wall: early aneurysmal lesion and saccular aneurysm.
Kang et al19 demonstrated that intravenously injected blood coagulation factor XIII causes the proliferation of smooth muscle cells in experimental aneurysms. Although factor XIII is involved in wound healing by forming stable fibrin clotting and by stimulating migration and proliferation of fibroblasts,31 the promoting mechanism of factor XIII to smooth muscle cell proliferation remains unclear. However, their data suggest that the administration of some growth factors may induce the proliferative response resulting in the repair of cerebral aneurysms.
Basic FGF is a pluripotent growth factor that is involved in various processes of the growth and differentiation of mesodermal and neuroectodermal cells.13 Basic FGF is synthesized by endothelial cells14 32 and smooth muscle cells,33 and it is mitogenic for both.14 34 35 For these reasons, it has been postulated that basic FGF may play an important role in the pathogenesis of atherosclerotic vascular lesions.35 Lindner and coworkers15 demonstrated that basic FGF was localized within normal rat aorta and that the smooth muscle cells of rat carotid artery expressed mRNA of basic FGF. Moreover, they showed that the smooth muscle cell proliferation soon after arterial injury was diminished by antibodies to basic FGF.16 On the other hand, systemic administration of basic FGF enhances the proliferation of endothelial cells18 as well as smooth muscle cells15 in the balloon-injured carotid artery. However, in arterial wall covered with an intact endothelium, exogenous basic FGF does not increase smooth muscle cell proliferation.15 To the contrary, the endothelial cells were reported to show degenerative and regenerative changes in experimental cerebral aneurysms.3 5 6 These observations indicate that basic FGF is an alternative mitogen to be administered to induce the proliferative response in experimental cerebral aneurysms.
The present study clearly demonstrates that the systemic administration of basic FGF causes the proliferative change in early aneurysmal lesions. In addition, it was immunohistochemically confirmed that the proliferated cells were not endothelial cells but smooth muscle cells. The reasons why exogenous basic FGF promotes the proliferation of only smooth muscle cells and not endothelial cells are unclear. However, a monolayer of endothelial cells is preserved on the inner surface of early aneurysmal lesions in accordance with previous studies.2 3 6 26 Therefore, the proliferation may take place because of characteristics of endothelial cells in that they always grow as a monolayer and are subject to contact inhibition, even though the precise mechanism of this also remains unclear.
For administration of basic FGF to be useful in medical treatment for cerebral aneurysms, it is essential to prove its efficiency in treatment of saccular aneurysms of rats, which correspond to angiographically visible human cerebral saccular aneurysms. However, the present study did not demonstrate this efficiency, possibly due to the smaller doses of basic FGF. We administered 6 µg/100 g body wt of basic FGF to the low-dose group and 15 µg/100 g body wt (about 60 µg per whole body) to the high-dose group. These doses are relatively small compared with the 120 to 192 µg per whole body used in previous studies investigating the effects of this mitogen in rat denuded artery models.15 18 In the low-dose group of the present study, no apparent proliferative response was observed, even in the early aneurysmal lesions. This study also indicates the dose dependency of the effectiveness of exogenous basic FGF. To determine the optimal intravenous basic FGF dose needed to repair apparent saccular aneurysms, the present study is only preliminary. However, the optimal dose in rats may be more than 15 µg/100 g body wt. In addition to optimal dose, there are many problems yet to be clarified, including the duration of the effect of basic FGF and the behavior of this mitogen in arteriosclerotic lesions, which in humans often coexist adjacent to cerebral aneurysms. Many more experimental results should be evaluated before the administration of basic FGF is considered a safe and effective therapy for cerebral aneurysms.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Reprint requests to Kazuya Futami, MD, Department of Neurosurgery, Kanazawa University School of Medicine, 13-1, Takaramachi, Kanazawa 920, Japan.
Received May 9, 1995; revision received June 13, 1995; accepted June 13, 1995.
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