(Stroke. 1999;30:1657-1664.)
© 1999 American Heart Association, Inc.
Original Contributions |
Fibrinogen and Vascular Smooth Muscle Cell Grafts Promote Healing of Experimental Aneurysms Treated by Embolization
Correspondence to Dr Jean Raymond, Centre de recherche du CHUM and Radiology Department, University of Montreal Medical Center, Hôpital Notre-Dame, 1560 Sherbrooke St E, Montreal, Québec, H2L 4 M1, Canada. E-mail: notredame.radiologie{at}ibm.net
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Background and Purpose—Residual necks and recurrences frequently occur after endovascular treatment of cerebral aneurysms. Addition of fibrinogen and vascular smooth muscle cells (VSMCs) to the embolic material may promote healing of embolized aneurysms by increasing neointima formation at the neck.
Methods—Bilateral carotid aneurysms were constructed with venous pouches in 31 dogs. Aneurysms were packed intraoperatively with bare Gelfoam sponges, sponges treated with fibrinogen, or fibrinogen sponges seeded with the animal's own VSMCs or peripheral blood mononuclear cells. Animals were killed after angiography at 3 weeks, and morphometric studies were performed to measure the thickness of the neointima at the neck of treated lesions. Angiographic results and mean thickness of neointimas were compared using ANOVA. In 8 animals, 1 aneurysm was embolized with sponge seeded with VSMCs transduced by adenoviral infection to express a fluorescent protein (green fluorescent protein), and gene expression was monitored for 4, 7, 14, and 21 days by fluorescent microscopy.
Results—Aneurysms treated with sponges seeded with VSMCs had significantly thicker neointimas and were more completely obliterated at 3 weeks than control aneurysms treated with fibrinogen sponges. Peripheral blood mononuclear cells could not reproduce these findings. Sponges treated with fibrinogen alone promoted formation of a thicker neointima than bare sponges. Transduced cells transplanted into in vivo aneurysms still expressed green fluorescent protein at 3 weeks.
Conclusions—VMSC grafts can improve healing of experimental aneurysms treated by embolization. Transplantation of cells transduced to express a foreign gene opens the way for in situ gene therapy for cerebral aneurysms.
Key Words: cerebral aneurysm • cerebrovascular disorders • pathology • muscle, smooth • dogs
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Introduction |
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Recurrences after embolization of cerebral aneurysms pose a potential risk of late rebleeding, and this problem is limiting the widespread application of endovascular treatment.1 2 3 4 Potential avenues to improve morphological results include strategies to increase aneurysmal thrombosis and biomolecular or cellular interventions designed to promote healing mechanisms at the neck of embolized aneurysms.5 6 There is a general pattern of wound healing in the vessel wall: Coagulation, inflammation, migration, and proliferation of vascular smooth muscle cells (VSMCs) with synthesis and deposition of extracellular matrix (ECM) are responsible for vessel integrity and vascular repair phenomena.5 6 7 8 9 10 11 Because the cellular events responsible for healing of aneurysms seem to follow this pattern, VSMC grafts could be considered to promote early formation of a thicker, stronger neointima, hopefully resulting in a more permanent obliteration of aneurysms after embolization.5
We developed an aneurysm model that uses intraoperative packing with collagen sponges5 6 and have shown that complete healing of porcine aneurysms involves VSMCs, which form a thick neointima. When the same model is used in dogs, recurrence, associated with deficient neointima formation, is the rule.5 12 13 Although the exact causes of deficient healing remain speculative, we hypothesized that in situ autologous VSMC grafts may promote healing after embolization. We found support for this hypothesis by comparing the thickness of the neointima formed at the neck of grafted aneurysms with the one found in contralateral control aneurysms in the same animals. Because the technique we used to graft cells also involved a fibrinogen matrix, the potential effects of this protein per se on neointima formation are also demonstrated. To prove retention and viability of grafted cells, we transplanted cells transduced to express a reporter gene, green fluorescent protein (GFP),14 and monitored gene expression for up to 3 weeks in vivo by fluorescent microscopy.
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Materials and Methods |
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Preparation of VSMC Grafts and Control Sponges
VSMCs were harvested from the left femoral artery of each dog using the explant technique, cultured, and expanded as previously described.5 Gelfoam blocks measuring 15x20x7 mm were cut and hydrated in the autoclave for 10 minutes in PBS and then incubated for 15 minutes in DMEM supplemented with 10% FBS containing fibrinogen (2 mg/mL). Gelfoam fragments were placed in 12-well plates with 1 mL of DMEM-fibrinogen, and 2x106 cells suspended in 200 µL of DMEM were added to each well. Plates were incubated at 37°C for 2 hours, and the gel containing cells were transferred to a 6-well plate containing an excess amount of fresh DMEM with 10% FBS. Free-floating sponges seeded with VSMCs were cultured in DMEM and 10% FBS for 1 week before in vivo transplantation. Three types of control sponges were prepared for comparison. Sponges seeded with peripheral blood mononuclear cells (PBMCs) were prepared by injection into the fibrinogen sponges of 2x106 PBMCs isolated by gradient centrifugation with Ficoll from 15 mL of blood collected from the same animal.15 Fibrinogen sponges were prepared with DMEM containing 2 mg/mL of fibrinogen as described above but without adding cells to the matrix. These 2 types of control sponges were prepared simultaneously with VSMC sponges and similarly kept in vitro for 1 week before transplantation. Bare Gelfoam sponges were simply hydrated for 10 minutes in PBS 2 hours before the surgical procedure.
In Vitro Gene Transfer and Expression
VSMCs were infected by incubation for 2 hours at 37°C with
adenovirus expressing GFP for a multiplicity of infection of 150.
Replication-defective adenoviral vectors that express the GFP gene were
kindly supplied by Dr Bernard Massie (Biotechnology Research Institute,
National Research Council of Canada).14 Transduced cells
cultured in Gelfoam as previously described were transplanted into in
vivo aneurysms. For each sponge implanted in vivo, 2 series of
identical sponges were studied in vitro; 1 was studied at the time of
transplantation, and the other was kept in vitro until the time of
killing. GFP expression was detected by fluorescence microscopy
on in vitro sponges as well as on fresh in vivo specimens after axial
sections of the aneurysms were obtained at 4, 7, 14, and 21
days (n=2 each); these were compared with sponges and aneurysms
seeded with untransduced cells.
Animal Model
The lateral wall/venous pouch carotid aneurysm model
embolized with collagen sponges has been described
elsewhere.5 6 Protocols for animal experimentation were
approved by the Conseil interne de protection des animaux of the
University of Montreal Research Center and in accordance with the
guidelines of the Canadian Council on Animal Care. We used adult
mongrel dogs weighting 20 to 25 kg. All procedures were performed with
the animals under general anesthesia. Dogs were sedated
with an intramuscular injection of acepromazine (0.1 mg/kg),
glycopyrrolate (0.01 mg/kg), and butorphanol (0.1 mg/kg), followed by
intravenous injection of thiopental (15 mg/kg). After
endotracheal intubation, dogs were ventilated with a Harvard respirator
and kept under anesthesia with 2% isoflurane.
Postoperative analgesia was provided with a Fentanyl skin patch for 3
days. A 2-cm segment of the left femoral artery was resected after
proximal and distal ligation and transferred to cold DMEM supplemented
with 10% FBS for primary cultures of VSMCs. Four to six weeks later,
bilateral common carotid aneurysms were constructed and
embolized intraoperatively with Gelfoam fragments
as described.5 In brief, lateral wall aneurysms
were constructed on each common carotid artery using the technique of
German and Black as modified by Graves et al.16 Two
segments of the same external jugular vein were harvested. After
temporary occlusion of the common carotid artery, an oval 5-mm
arteriectomy was created in the arterial wall, to which the
open venous pouch was sutured with 8-0 prolene. One 8x8-mm Gelfoam
fragment (with or without fibrinogen or cells) was inserted inside the
aneurysm to completely occlude it. Treated and control sponges
were placed in a random manner, and the surgeon was blinded to the
content of the sponge. Angiography from the femoral route was performed
immediately after surgery while the animals were still under general
anesthesia to study the symmetry of morphological results
of the 2 aneurysms. Dogs were allowed to consume their normal
diet, and their activities were not restricted. They were
anesthetized and carotid angiography was performed before
killing (by barbiturate overdose) at 4 days (n=2) and at 1 (n=2), 2
(n=2), or 3 weeks (n=20) to document the degree of aneurysmal
obliteration and to detect arterial stenosis. Three
control animals were followed up for 3 months before angiography and
killing. The common carotid artery was dissected after killing. The
wall of the carotid artery was longitudinally opened opposite of the
aneurysm to visualize the luminal surface of the
neointima covering the neck of the aneurysm. A 2-cm
axial section of the aneurysm, taken from the middle of the
neck, was sliced from the specimen, examined for the presence of
fluorescent cells (when appropriate), and used for
neointima measurement after formalin fixation and paraffin
embedding. The remainder of the aneurysm was frozen at -70°C
in Fisher's tissue embedding medium for additional studies, including
fluorescence microscopy and immunohistochemical studies of
cryosections.
Healing at the neck of aneurysms was assessed in vivo by angiography at 3 weeks, and results were scored according to a classification previously described.3 5 17 A score of 0 indicated complete obliteration; 1, "dog ears"; 2, recurrent neck; and 3, recurrent aneurysm.
Pathological Studies
The neointimal layer at the neck of each
aneurysm was measured (without knowledge of the nature of the
sponge) in 5 locations after formalin fixation, axial sectioning, and
staining with hematoxylin, phloxine, and saffron (HPS) and with
Movat's pentachrome; this method was developed and
standardized in our laboratory.5 6 Immunohistochemical
methods were used to characterize neointimal cells and
cells inside the sponge at different time intervals after embolization
using antibodies to smooth muscle 
-actin and von Willebrand
factor. Morphometric data were analyzed using a computerized
image analysis system.
Statistics
Data were analyzed using ANOVA for repeated measures,
applied to an incomplete block design with nesting: Because each dog
received 2 types of treatments, applied to 2 separate
aneurysms, dogs were treated as blocks, in which treatments
were considered nested. Stepwise linear regression was used to
investigate the relationship between angiographic score (dependent
variable) and type of treatment and neointima thickness
(independent variables).
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In Vitro Studies
VSMCs were cultured from 100% of femoral artery explants in all animals. These cells were
-actin positive and proliferated to yield
6 to 8x106 cells in 4 weeks. VSMCs could not
adhere to bare Gelfoam sponges in vitro. When seeded on a collagen
sponge treated with fibrinogen, VSMCs adhered to the matrix.
Contraction of the matrix by VSMCs around the sponge led to formation
of an organized structure that looked like an "in vitro
neointima"(see Figure 1A
).
VSMCs were morphologically intact after adenoviral infection and still
expressed -actin (Figure 1B). Cell proliferation was
unaffected by adenoviral infection, with the multiplicity of infection
varying from 100 to 1000 (data not shown). GFP expression remained
strong in all specimens and at all times (4 days and 1 to 4 weeks)
after infection and seeding onto collagen sponges (Figure 1C and 1D).
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In Vivo Studies
Angiographic Results
Angiographic results are summarized in the Table. There was no
significant difference in mean angiographic scores at time 0 between
aneurysms or between groups of animals. The angiographic score
of lesions treated with bare sponges significantly increased at 3
weeks, confirming the tendency for recurrence of this model
(P<0.001) (Figure 2). The
angiographic score of aneurysms treated with VSMCs decreased
slightly at 3 weeks, but this trend did not reach statistical
significance (P=0.36). At 3 weeks, aneurysms were
significantly more obliterated with VSMC grafts (score of 1.13)
than with fibrinogen sponges (1.92; P=0.01) or bare sponges
(2.39; P=0.001). Aneurysms treated with fibrinogen
sponges had a significantly lower score than those treated with bare
Gelfoam sponges (P=0.05). All aneurysms treated with
bare sponges and followed up for 3 months showed large
recurrences (Figure 3C).
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Histological Findings
In aneurysms treated with bare Gelfoam sponges, a very
thin and incomplete neointima, consisting of VSMCs, ECM,
and collagen, was consistently found at the surface of the
embolic agent at 3 weeks (Figure 3
). The inflammatory reaction was
minimal. Addition of fibrinogen led to thrombus formation at the
surface of the sponge (Figure 4). This
thrombus was invaded by VSMCs, ECM, and collagen fibers. Inflammatory
changes were more extensive. Aneurysms treated with VSMC grafts
had a thick cellular neointima. Most cells were -actin
positive, but inflammatory cells could also be recognized (Figure 5). Control aneurysms followed up
for 3 months showed large recurrences; the
neointima at the surface of the sponge, now compressed at
the fundus of the aneurysm, remained thin (Figure 3C).
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Measurements of the thickness of the neointima at the neck
of treated aneurysms are summarized in the Table. There
was a significant correlation between angiographic scores and
neointima measurements at 3 weeks: the thicker the
neointima, the lower the angiographic score
(P=0.047). There was a significant difference between
treatments (P<0.001). Aneurysms treated with a VSMC
graft had the thickest neointimas (342.5±7 µm),
followed by collagen sponges treated with fibrinogen (97.6±6
µm). PBMC grafts could not reproduce this finding (37.5±15
µm). Aneurysms treated with bare Gelfoam sponges had the
thinnest neointimas (36.1±6 µm). These differences
were statistically significant (P<0.002).
In Vivo Expression of GFP
Numerous GFP-positive cells could be detected on fresh specimens
at 4 days and at 1, 2, and 3 weeks (n=2 each), whereas no
fluorescence (except for background) was seen in control
aneurysms of the same animals (Figure 6).
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Aneurysm Models
Animal models have been designed to study healing mechanisms after embolization of aneurysms. We developed a model that uses collagen sponges (Gelfoam) as an embolic agent5 6 . Gelfoam has been used to support vascular cell growth in vitro18 as well as to transfer engrafted cells in vivo.19 20 Fundamental histopathological findings with Gelfoam do not differ significantly from those found with the coil model.5 12 21 When the collagen sponge model is used in dogs, aneurysms do not heal at 3 weeks and the neointima formed at the neck of treated lesions is thin and incomplete. We have shown that recurrence, as assessed by angiography, is the rule at 3 months. This canine lateral wall aneurysm model may thus offer an opportunity to study factors responsible for recurrences and serve as a tool to test our therapeutic strategies in an animal that reproduces the clinical problem.
Aneurysmal Healing, VSMC Grafts, and Neointima
Thickness
We found a significant correlation between angiographic
scores and neointima thickness in this canine model. When
bare Gelfoam sponges were used to embolize aneurysms,
there was a significant increase in the angiographic score from time 0
to 3 weeks, and the neointima was very thin. VSMC grafts
prevented this tendency for recurrence, and the
neointima at 3 weeks was significantly thicker. We
previously showed that the neointima that forms at the
surface of the embolic agent at the neck of treated aneurysms
at 3 weeks is thick in animals prone to heal and thinner or absent in
animals with a propensity for recurrences.5
Analogous to other deficient healing systems, such as skin ulcers or
pseudoarthrosis, the recurrences of canine aneurysms
seen at 3 months were the consequence of deficient healing early in the
process. Therefore, late results could be improved by stimulating
healing mechanisms in the first weeks after embolization. Autologous
cell grafts allowed us to increase the thickness of the
neointima formed at the neck of canine aneurysms
from values associated with recurrence to levels approaching
those found in pigs, animals that routinely heal.5 21 This
strategy may thus favor healing after embolization, but whether it will
effectively prevent long-term recurrences remains to be
proven.
Thrombus, Provisional Matrix, and Neointima Formation
The neointima was significantly thickened by the
addition of fibrinogen to sponges. Fibrinogen may provide a provisional
matrix that is lacking in dogs. Alternatively, the fibrinogen matrix
may serve as a more thrombogenic surface. In either case, the
provisional fibrin or fibrinogen matrix may be essential as a physical
support for cell adhesion and migration, which are basic steps in
neointima formation. Thrombotic phenomena have been evoked
to explain differences in the magnitude of postangioplasty
restenoses between dogs and pigs.10 Similarly,
thrombus formation at the surface of the embolic agent may be an
important factor to explain differences in neointimal
thickness after embolization between these 2 species. Furthermore,
fibrinogen contains peptide sequences that are involved in cellular
adhesion.22 23 24 This property may explain why VSMCs could
not be cultured on bare Gelfoam sponges but attached to the fibrinogen
gel used in the formation of the grafts. The opportunity to improve
morphological results of embolization by providing a more thrombogenic
surface or by coating embolic agents with proteins that may favor
cellular adhesion or migration is an appealing avenue for future
developments.2
VSMC Grafts and Vessel Wall Healing
Although there is still debate about the precise origin and nature
of cells responsible for neointima formation, VSMCs are
virtually the only cells present in the arterial media.
These cells have been described as multifunctional mesenchymal cells
that can reexpress different phenotypes, including cells
with the ability to secrete such ECM proteins as
collagen.9 10 11 25 26 27 28 29 30 31 32 33 34 35 36 Immunohistochemical
analyses performed 1, 2, 3, and 4 weeks after embolization have
shown that most cells infiltrating the aneurysms and forming
the neointima are -actin positive.5 In
canine arteries, the media is composed of at least 2 cell populations.
Type 1 cells are contractile VSMCs, which do not proliferate in vitro.
Type 2 cells are capable of proliferating and expressing smooth muscle
-actin in culture and are probably responsible for
neointima formation.36 In vitro conditions
select for "type 2 cells" in outgrowths of medial
explants.36 In this experimental protocol, VSMCs cells
could be harvested from 100% of femoral artery explants; these cells
were -actin positive at 2 weeks in vitro, proliferated in 10%
serum, and could be grown on Gelfoam sponges treated with fibrinogen.
The mechanisms responsible for increased neointima
formation after VSMC grafting are not precisely known, but PBMCs did
not cause the same effect. It is conceivable that grafted cells
directly participated in neointima formation by
proliferating and secreting ECM. However, most neointimal
cells were GFP negative at 2 and 3 weeks, suggesting that either a
subpopulation of cells had proliferated and progressively lost the GFP
gene (which is episomal) or, more likely, that most cells composing the
thicker neointima had migrated from the host rather than
from the graft. It is also possible that grafts were more thrombogenic
than fibrinogen sponges. Different mechanical properties of the sponges
(VSMC-seeded sponges were slightly "contracted") or a larger number
of cells in VSMC sponges (which may proliferate during the 1-week
incubation period) are other hypotheses that cannot be excluded. These
mechanisms were not elucidated, but infection of cells with a
GFP-expressing adenovirus did provide a means to monitor retention and
viability of grafted cells in vivo.
VSMCs Can Be Genetically Modified Before In Vivo
Transplantation
Vascular cells have previously been induced to express a
reporter gene.27 37 38 39 40 The potential efficiency of
adenovirus-mediated gene transfer is supported by cell culture studies:
VSMCs have been infected with efficiencies approaching
100%.37 41 42 43 Adenovirus-mediated gene transfer into
normal arteries may result in prolonged vascular cell activation,
inflammation, and neointimal hyperplasia.44
This phenomenon may interfere with protocols designed to treat
proliferative diseases but may be helpful in our attempt to stimulate
neointimal hyperplasia. The ex vivo cell-mediated method
ensures a high efficiency of gene transfer into a specific target cell
and decreases immunogenicity.39 41 45 Viable
fluorescent cells were recovered in vivo 21 days after
embolization. Such a system may thus permit development of other
strategies to improve morphological results of endovascular treatment,
such as cell-mediated local delivery of biologically active molecules.
These could include matrix proteins, molecules involved in cell
adhesion, coagulation or thrombolytic modulators, or
growth factors that have been shown to favor neointima
formation.6 46 47 We previously showed that the
neointima at the neck of treated aneurysms could be
significantly thickened at 2 weeks by local delivery of growth factors
or platelet extracts.6 The fact that transduced cells
still expressed a foreign gene 3 weeks after transplantation supports
the hypothesis that this technique could be effective in delivering a
desired peptide or protein during this critical period, if not longer.
This strategy may not necessitate transplantation of a large number of
cells and, as such, may be more realistically accomplished using
current technologies. The fibrinogen-matrix method used to seed
collagen sponges can be used to seed Guglielmi detachable coils, but a
significant number of cells may be lost during coil manipulations.
Inclusion of cells within a polymeric embolic agent may be more
efficient for delivering cells by endovascular
techniques.48 49 50 Of course, VSMC grafts cannot be used
immediately after subarachnoid hemorrhage but may be
considered for recurrences or elective treatment of unruptured
aneurysms. Transplantation of genetically modified cells can,
for the time being, provide a model to study the effects of
overexpression of molecules that may promote or decrease
neointima formation in experimental aneurysms. This
investigational tool may advance our understanding of vascular healing
phenomena in aneurysms treated by embolization.
Conclusion
Deficient healing of canine aneurysms and
neointima thickness at the neck of treated lesions are
linked. In aneurysms treated with bare Gelfoam sponges, the
neointima is very thin and angiographic scores tend to
increase even at 3 weeks. Deficient healing is associated with
insufficient thrombosis and can be partly compensated by adding
fibrinogen to the embolic agent. The neointima at the neck
of experimental aneurysms could be significantly increased by
VSMC grafts. Autotransplantation of VSMCs could significantly improve
angiographic results at 3 weeks. Transplantation of transduced cells is
feasible, and gene expression persists at least 3 weeks, opening the
wayto gene therapy for cerebral aneurysms. This
strategy could also help us to understand healing phenomena after
embolization of aneurysms.
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Acknowledgments |
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This study was partially supported by a grant from the Fonds de la Recherche en Santé du Québec and la Fondation des Maladies du C
ur du Québec. We thank Rose-Mai Roy for expert
secretarial assistance. |
Footnotes |
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Centre de recherche du CHUM and Radiology Department, University of Montreal Medical Center, Hôpital Notre-Dame, Montreal, Québec, Canada.
Received February 16, 1999; accepted May 17, 1999.
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Editorial Comment
Department of Neurosurgery, University of California, Davis, Sacramento, California
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Clinically, the methods described in this article may not be very relevant, because it appears that aneurysm obliteration with Guglielmi detachable coils is more efficacious than with other methods1 . Nevertheless, the authors describe important principles that may someday be clinically applicable. Protein coating has already been reported for Guglielmi detachable coils, but this study reached farther. Not only can viable cells be incorporated in the gelfoam, they can also be genetically altered in vitro before implantation.
I believe inducing endothelial growth is actually more important than enhancing the thrombogenicity of the implants. So far, I have seen more problems due to late (1 week) thrombus spreading from the implant than aneurysm recurrence or rebleeding, and with early reendotheliazation of the aneurysm neck, such a complication could obviously be prevented.
The debate about the preferred treatment of cerebral aneurysms is far from settled. Although operative treatment has remained more or less the same for the past 20 years, endovascular treatment is still in full development and furthermore, advances can be expected. This article provides a glimpse into possible future, exciting directions.
Received February 16, 1999; accepted May 17, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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- Macdonald RL, Mojtahedi S, Johns L, Kowalczuk A. Randomized comparison of Guglielmi detachable coils and cellulose acetate polymer for treatment of aneurysms in dogs. Stroke. 1998;29:478–486.
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