(Stroke. 2001;32:1036.)
© 2001 American Heart Association, Inc.
Original Contributions |
Molecular Anatomy of an Intracranial Aneurysm
Coordinated Expression of Genes Involved in Wound Healing and Tissue Remodeling
From the Department of Human Genetics, Graduate School of Public Health (D.G.P., E.H-O., R.E.F.), Department of Hematology/Oncology, School of Medicine (A.B.), and Department of Neurosurgery, School of Medicine (A.B.K., H.Y.), University of Pittsburgh (Pa).
Correspondence to David G. Peters, PhD, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261. E-mail dpeters{at}helix.hgen.pitt.edu
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Abstract |
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Background and Purpose—Approximately 6% of human beings harbor an unruptured intracranial aneurysm. Each year in the United States, >30 000 people suffer a ruptured intracranial aneurysm, resulting in subarachnoid hemorrhage. Despite the high incidence and catastrophic consequences of a ruptured intracranial aneurysm and the fact that there is considerable evidence that predisposition to intracranial aneurysm has a strong genetic component, very little is understood with regard to the pathology and pathogenesis of this disease.
Methods—To begin characterizing the molecular pathology of intracranial aneurysm, we used a global gene expression analysis approach (SAGE-Lite) in combination with a novel data-mining approach to perform a high-resolution transcript analysis of a single intracranial aneurysm, obtained from a 3-year-old girl.
Results—SAGE-Lite provides a detailed molecular snapshot of a single intracranial aneurysm. These data suggest that, at least in this specific case, aneurysmal dilation results in a highly dynamic cellular environment in which extensive wound healing and tissue/extracellular matrix remodeling are taking place. Specifically, we observed significant overexpression of genes encoding extracellular matrix components (eg, COL3A1, COL1A1, COL1A2, COL6A1, COL6A2, elastin) and genes involved in extracellular matrix turnover (TIMP-3, OSF-2), cell adhesion and antiadhesion (SPARC, hevin), cytokinesis (PNUTL2), and cell migration (tetraspanin-5).
Conclusions—Although these are preliminary data, representing analysis of only one individual, we present a unique first insight into the molecular basis of aneurysmal disease and define numerous candidate markers for future biochemical, physiological, and genetic studies of intracranial aneurysm. Products of these genes will be the focus of future studies in wider sample sets.
Key Words: cerebral aneurysm • gene expression • stroke, hemorrhagic
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Introduction |
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Intracranial "berry" aneurysms are saccular dilatations of an intracranial artery most often located at a branch point of a major artery on the circle of Willis. There is significant evidence that susceptibility to cerebral aneurysms has a significant genetic component.1 2 Each year in the United States, >30 000 people suffer a ruptured intracranial aneurysm that results in a particularly severe form of stroke. Among those individuals who suffer a ruptured intracranial aneurysm, 50% die at the time of rupture or shortly thereafter, and 25% suffer permanent disability, including paralysis and loss of speech, vision, and motor coordination. The remaining 25% are at increased risk of stroke, recurrent bleeding, or other complications. In contrast, operative repair of an unruptured aneurysm has a mortality of <2.5% and morbidity of <6%,3 making treatment during this stage much more palatable. Unruptured aneurysms are a common incidental finding at autopsy and during cerebral angiography and have an estimated prevalence in the general population of 1% to 6%.3
While the incidence of other types of stroke has declined in recent decades, primarily because of improved detection and management of hypertension, the incidence of subarachnoid hemorrhage has remained relatively constant. Despite the high incidence of intracranial aneurysm and the catastrophic consequences of rupture, relatively little is understood with respect to intracranial aneurysm molecular pathology and pathogenesis. This lack of information has severely hampered efforts to identify individuals at risk of an intracranial aneurysm and to define novel points of therapeutic intervention and is largely due to the difficulty in obtaining suitable aneurysmal tissue specimens for use in these analyses. The few studies that have attempted to investigate the molecular basis of intracranial aneurysm have focused on a limited number of biological markers that have been studied in isolation rather than in a global context.4 5 In consequence, previous studies have been significantly biased by a presupposition of intracranial aneurysm pathobiology, and, to our knowledge, no previous semiquantitative comprehensive sampling technique has been applied.
Recent developments in technologies that provide comprehensive, or "global," assays for transcription are yielding detailed information regarding how cell types or whole tissues respond to defined stimuli or define pathological state at the level of transcription. One such approach to defining global transcriptional profiles is Serial Analysis of Gene Expression (SAGE).6 This is a powerful technique that allows comprehensive analysis of gene expression in a specific cell or tissue type and, unlike hybridization-based approaches using microarrays,7 8 is not limited to the analysis of previously identified genes or biased by presumed association between genes of interest and pathobiology. Unfortunately, however, SAGE requires the availability of large quantities of high-quality mRNA, which are not commonly available when studying human disease, particularly intracranial aneurysm. To overcome this, we have recently developed a modification of SAGE that requires only very small (as little as 50 ng) quantities of input total RNA. We call this approach "SAGE-Lite."9
SAGE-Lite was used in the present study to construct semiquantitative databases of expressed genes in a sample of intracranial aneurysm and superficial temporal artery (STA) obtained from a single individual (internal control). Comparisons made between these databases reveal many genes whose expression is elevated in dilated aneurysmal tissue relative to undilated control STA. This provides a detailed molecular snapshot of intracranial aneurysm and indicates that arterial dilation results in a highly dynamic cellular environment in which high levels of expression of genes previously associated with wound healing and tissue/extracellular matrix (ECM) remodeling take place. We describe the first comprehensive and unbiased semiquantitative analysis of the molecular pathology of an intracranial aneurysm. Although these data are derived from analysis of a single intracranial aneurysm case, this preliminary work identifies candidate genes for use in future biochemical and population-based genetic studies of aneurysm pathogenesis and rupture.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue
A 3-year-old girl presented with a new-onset seizure, and CT scan revealed an intracerebral hemorrhage centered in the sylvian fissure. Angiography demonstrated multiple aneurysms on the distal middle cerebral artery (Figure 1
). Four days after admission to Presbyterian
University Hospital of Pittsburgh, the patient underwent
craniotomy for excision of the aneurysmal
segment of the middle cerebral artery. Histology confirmed these to be
true berry aneurysms and not pseudoaneurysms, as seen
with mycotic lesions. Ethical approval for this study was obtained from
the institutional review board committee of the University of
Pittsburgh.
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SAGE-Lite
SAGE-Lite was performed as described
previously.9 Tissue samples
were obtained (with institutional review board approval and after
informed consent was obtained) in the operating room and snap-frozen on
dry ice, and RNA was extracted by the Trizol method (Life
Technologies). mRNA was reverse-transcribed (from 100 ng of total RNA)
with the use of Superscript II (Life Technologies). First-strand
synthesis was primed with a biotinylated oligo(dT) primer
(5'-AAGCAGTGGTAACAACGCAGAGTACT(30)VN-3' (N=A, G,
C, or T; V=A, G, or C) in the presence of a second
oligonucleotide (5'-AAGCAGTGGTAACAACGCAGAGTACGCGGG),
which acts as a second template during strand
switching.10 First-strand
cDNA was amplified with the use of the Advantage cDNA Synthesis System
(Clontech) according to the manufacturer’s instructions using the same
oligonucleotides employed during first-strand
synthesis.9
Dot Blotting and Hybridization
First-strand cDNA (prepared as described above) was
amplified with the use of the Advantage cDNA Synthesis System
(Clontech) according to the manufacturer’s instructions using a single
primer (5-AAGCAGTGGTAACAACGCAGAGT). Amplified cDNA was denatured by
heating at 95°C for 10 minutes in a total volume of 500 µL and a
final concentration of 0.4 mol/L NaOH, 0.1 mol/L EDTA (pH 7.5). cDNAs
were then vacuum blotted onto Zeta Probe GT membrane (Bio-Rad), fixed
by heating at 80°C for 2 hours, hybridized overnight at 65°C in 0.5
mol/L Na2PO4 and 7% SDS,
and washed in 40 mmol/L
Na2PO4 and 5% SDS at
65°C.
Statistical Analysis
To prioritize tags for further analysis, we
ranked tags in descending order of the importance of the difference
between the 2 samples. The importance of the difference was assessed by
applying a variance-stabilizing transformation to the tag frequencies
and then taking the difference between the transformed frequencies in
the 2 samples. Because of the exploratory nature of our
analysis goals, we did not attempt to develop hypothesis tests
to assess the statistical significance of the differences for
particular tags. The transformation we used is of the form
ln(f+k),
where f is the tag frequency,
k is a constant, and ICA
indicates intracranial aneurysm, so that the tags are ranked in
order of
ln(fSTA+k)-ln(fICA+k).
The transformation is necessary so that all measurements will have
constant variance. It seems clear both from mathematical theory and
from experimental data that the raw frequencies have higher variance
for larger abundance tags. This means that if the data were ranked on
the untransformed differences between the frequencies, high-abundance
tags would rise to the top of the list too easily. Similarly, if the
data were ranked on the ratio of the frequencies, low-abundance tags
would rise to the top of the list too easily. The particular
transformation we chose is not necessarily optimal but seems to work
well in practice. The value of
k used in the transformation is
a calibration constant that essentially regulates the relative ease
with which high- and low-abundance tags can rise to the top of the
list. For this data set, we expected a large number of differences
between the samples, and therefore we somewhat arbitrarily set
k=0.001, a value that has
performed well over a variety of data
sets.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SAGE-Lite Analysis of Gene Expression in Intracranial Aneurysm and STA
SAGE-Lite was used to compare gene expression patterns in a sample of intracranial aneurysm with STA from the same individual, a 3-year-old girl who underwent craniotomy to resect multiple ruptured and unruptured aneurysms in the middle cerebral artery (Figure 1
). The STA sample was also removed during this
procedure. We sequenced 11 495 and 7297 SAGE tags from the intracranial aneurysm and STA, respectively, and compiled tissue-specific databases of expressed genes. In total, we verified the expression of 4924 and 3552 distinct genes in the intracranial aneurysm and STA samples, respectively. In summary, 31% of the 100 most frequently detected SAGE tags in the intracranial aneurysm are derived from genes that are differentially regulated, with a >5-fold difference in expression relative to STA. This includes 11 tag species that were undetectable in the STA. Of the top 100 intracranial aneurysm tags, 25% do not match previously characterized gene entries in the GenBank database. Similarly, 29% of the 100 most highly expressed genes in STA are differentially regulated, with a >5-fold difference in expression relative to intracranial aneurysm. Entire SAGE-Lite data sets are available as publicly accessible, downloadable spreadsheets at www.pitt.edu/~dgp.
Figure 2A shows the frequencies of each tag (number of times
the tag is observed divided by total number of tags sequenced in that
sample) in the 2 samples.
Figure 2B is an expanded view of the lower-frequency portion
of the same plot. Note that most of the lowest-frequency points
represent many tags. For example, 2041 tags were observed just
once in the STA sample and not at all in the intracranial
aneurysm sample.
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Table 1 is a list of the 25 tags that are overexpressed in
intracranial aneurysm and show the most significant differences
in abundance between intracranial aneurysm and STA. The list is
ranked in order of the differences between the transformed frequencies
in the 2 samples (see Materials and Methods).
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SAGE-Lite Indicates Extensive Tissue Remodeling
in Intracranial Aneurysm
There are a considerable number of genes whose
differential expression suggests that the intracranial aneurysm
is undergoing significant tissue remodeling (tag counts noted below are
shown in parentheses for intracranial aneurysm/STA). For
example, a variety of ECM constituents are highly overexpressed in
intracranial aneurysm, including the following: fibronectin
(443/4), collagen type III 
-1 (34/7), collagen type I -2 (20/1),
collagen type I -1 (17/1 and 16/0), collagen type VI -1 (13/1),
collagen type VI -2 (9/1), collagen type IV -1 (5/0), and elastin
(5/0).
In addition, numerous other factors known to be involved in
ECM turnover and cell migration and adhesion are highly expressed in
the intracranial aneurysm. These include tissue
inhibitor of metalloproteinase-3 (TIMP-3) (20/0), SPARC
(osteonectin) (29/0), "hevin" (6/0), connective tissue growth
factor (CTGF) (6/0), ß-galactosidase-binding lectin (26/7),
cdc-rel2a/PNUTL2 (14/0), vinculin (5/1), tetraspanin-5 (5/0), c-Abl
(7/0), ßig-h3 (6/0); osteoblast-specific factor-2 (OSF-2) (13/0), and
cathepsins B (13/1) and D (4/0). Note that observed numbers of
gene-specific tags are shown in parentheses (intracranial
aneurysm/STA). These data are summarized in
Table 2.
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The intracranial aneurysm is also the site of a
strong immune/inflammatory response. This is manifested by high levels
of expression of mRNAs encoding human leukocyte antigen (HLA) antigens,
including HLA-B44 (38/6), HLA-C (16/3), HLA-B (12/1), and
ß2-microglobulin (9/3), which are major histocompatibility complex
(MHC) class I markers. The intracranial aneurysm was also found
to express HLA-DP4 (8/0), HLA-Dw12 (7/0), and HLA-DR (163/17), which
are MHC class II markers, and high levels of mRNAs encoding IgG heavy
chain (33/0) and Ig
light chain (20/0). The high level of expression
of these mRNAs demonstrates a significant inflammatory and/or immune
response, which may be associated with infiltrating mononuclear cells
and is consistent with intracranial aneurysm undergoing
dramatic tissue remodeling. Whether this tissue remodeling is a direct
result of aneurysmal dilation and repair or is secondary to the
inflammatory response to an intraparenchymal bleed cannot be determined
in this limited analysis of one sample.
Confirmation of Differential Gene Expression
Patterns in Intracranial Aneurysm
Whole cDNA dot blotting was used to confirm
differential gene expression patterns of a subset of genes identified
by SAGE-Lite. These data are shown in
Figure 3.
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Discussion |
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We present here the first comprehensive molecular characterization of an intracranial aneurysm and compare its gene expression profile with that of a normal undilated vessel (STA). The use of the STA (an extracranial vessel) as the control vessel, although not ideal, is warranted by the fact that samples were obtained intraoperatively and not obtained postmortem. This approach ensures that RNA samples are freshly harvested and thereby avoids potential problems resulting from excessive RNA degradation that, in our experience, occurs when samples are harvested postmortem.
SAGE-Lite indicates an intracranial aneurysm pathology that is highly consistent with tissue injury, wound healing, and extensive ECM remodeling.
To ensure that the cDNA amplification step involved in SAGE-Lite is representative, we have previously performed comprehensive quality control checks to ensure that nonrepresentative amplification is minimal.9 In addition, the SAGE data contain numerous examples of groups of functionally complementary/overlapping genes that are overexpressed in the intracranial aneurysm at similar magnitudes. Some of these are summarized below, and these further support the accuracy of the data presented. Differential gene expression between intracranial aneurysm and STA was also confirmed for a number of markers using reverse transcriptase–polymerase chain reaction (data not shown).
By far the most abundantly expressed transcript in the intracranial aneurysm is fibronectin. This was present at much higher levels (approximately 100-fold) in the intracranial aneurysm sample relative to the STA. Fibronectin is a large dimeric glycoprotein found in the ECM of a variety of tissues and is involved in diverse cellular processes, including cell adhesion, cell migration, and repair. High levels of expression of fibronectin in intracranial aneurysm are consistent with a number of previous studies that describe the upregulation of fibronectin as a result of vascular injury11 and in response to hypertension.12 13 Furthermore, it has been suggested that fibronectin organization is altered in experimental cerebral aneurysms in rats.14
There are also dramatic differences in the levels of a variety of collagen genes expressed in the intracranial aneurysm, and increased aneurysm-specific transcription is observed for TIMP-3. These observations indicate that a high degree of ECM remodeling is taking place in the intracranial aneurysm. This is in general agreement with the previous findings of a number of investigators who have shown that matrix metalloprotease (MMP)-2 and -9 are present at high levels in aneurysmal tissue.4 5 We did not detect these MMPs expressed in either the intracranial aneurysm or STA samples, which may indicate that levels of expression of MMPs are low in these particular tissue samples.
Consistent with the above observations, a number of other tags representing factors thought to be involved in collagen metabolism are overexpressed in intracranial aneurysm. These include ßig-h3 and CTGF. ßig-h3 is a cell surface recognition peptide, which is inducible by transforming growth factor-ß (TGF-ß) and contains a putative binding site (RDG) for integrins. Although the exact function of this factor remains unclear, it may have a bridging function, linking or stabilizing the interactions of collagen with other ECM structures.15 16 Similarly, CTGF is a cysteine-rich peptide synthesized and secreted by fibroblastic cells after activation with TGF-ß that is thought to mediate TGF-ß–induced collagen synthesis.17 18
Other highly expressed aneurysm-specific markers include SPARC (osteonectin), which is a counteradhesive glycoprotein expressed in a variety of tissues, including vascular endothelium, smooth muscle, and fibroblasts. SPARC is known to inhibit endothelial cell adhesion and proliferation, and SPARC protein and mRNA have been shown to be increased in renal vascular injury.19 Indeed, it has been proposed that ECM remodeling is regulated in part by a specific interaction between SPARC and type I collagen.20 Interestingly, another acidic protein, designated hevin, that is found in the high endothelial venules of lymphoid tissues has antiadhesive properties and is highly related to SPARC.21 Like SPARC, hevin is expressed in the intracranial aneurysm and is absent in STA.
Other notable intracranial aneurysm–specific mRNAs include cdc-rel2a/PNUTL2,22 which belongs to an expanding family of GTP binding proteins, called septins, that are thought to be involved in cytokinesis23 ; vinculin, an adhesion plaque attachment protein; and c-Abl, a nonreceptor tyrosine kinase that is recruited, from the nucleus to focal adhesion sites, by cell adhesion to fibronectin and is thought to phosphorylate the focal adhesion protein paxillin. It is noteworthy that paxillin, an integrin, is a substrate for SPARC-induced tyrosine phosphorylation.24 Also overexpressed in intracranial aneurysm is ß-gal-binding lectin (Galectin-1), which is a matricellular protein that has recently been shown to be centrally involved in vascular smooth muscle cell proliferation.25
There are also a number of factors associated with tissue remodeling whose overexpression in intracranial aneurysm is consistent with ECM remodeling but somewhat less predictable. For example, OSF-2 is a transcription factor that is thought to be restricted to cells of the osteoblast lineage.26 OSF-2 has been implicated in the activation of collagenase-3 (MMP-13) during bone formation27 but, to our knowledge, has not been linked to arterial pathologies. Cathepsin B is a lysosomal cysteine protease involved in intracellular protein catabolism and is implicated in cancer28 and chronic inflammatory diseases of airways and joints. Cathepsin D is an aspartyl endoproteinase that is ubiquitously distributed in lysosomes.29 In addition to their protein-degrading function in lysosomes and phagosomes, these proteases activate precursors of biologically active proteins in prelysosomal compartments of specialized cells.30 Cathepsins are clearly implicated in tumor invasion and metastasis through the dissolution of ECM31 32 and have been used as prognostic markers for predicting metastatic breast disease. Despite the fact that this characteristic is consistent with tissue remodeling in the vasculature, cathepsins have not been a focus of attention with respect to arterial disorders, although they have recently been associated with the pathogenesis of abdominal aortic aneurysm.33 34
The fact that there is a considerable inflammatory/immune component in the intracranial aneurysm is also significant. Whether this is contributing to slow aneurysm growth and expansion or is part of a response to sudden and catastrophic dilation is unknown. It may also be a consequence of an inflammatory reaction, secondary to intraparenchymal hemorrhage after aneurysm rupture. From these preliminary data, derived from a single atypical sample, we are unable to delineate between these possibilities. As such, it will be vital to extend these studies to a wider sample set consisting of more typical examples of both ruptured and unruptured intracranial aneurysms. It will also be important to characterize specific cell types in these aneurysmal biopsies with the use of immunohistochemical techniques to gain a clearer understanding of this aspect of intracranial aneurysm pathology.
In summary, we have characterized, at high resolution, the molecular pathology of an intracranial aneurysm. Although preliminary and based on a single somewhat atypical case, these data are a valuable resource for designing future studies of both the pathology and pathogenesis of intracranial aneurysm in a wider sample set derived from more typical cases. Markers identified in this study may, after further characterization in a wider sample set, become potential targets for noninvasive screening and therapeutic interventions in the management of intracranial aneurysms. Furthermore, the recent results of the International Study of Unruptured Intracranial Aneurysms35 suggested that aneurysms <1 cm in diameter carry a very small risk of rupture. This has raised considerable controversy within the neurosurgical community since it is believed that there may be factors other than the size of the lesion that determine risk of rupture. Identifying dynamic aneurysms that are actively undergoing remodeling at a molecular level may prove to be an important determinant of risk of rupture. The same genes may also be regarded as candidates for use in population-based genetic association studies to identify individuals who are at risk of developing an intracranial aneurysm or at increased risk of rupture leading to subarachnoid hemorrhage.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (HL-44682), Copeland Foundation of Pittsburgh (D1999-0125), and University of Pittsburgh Cancer Institute.
Received August 9, 2000; revision received November 20, 2000; accepted December 15, 2000.
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W.I. Mangrum, F. Farassati, R. Kadirvel, C.P. Kolbert, S. Raghavakaimal, D. Dai, Y.H. Ding, D. Grill, V.G. Khurana, and D.F. Kallmes mRNA Expression in Rabbit Experimental Aneurysms: A Study Using Gene Chip Microarrays AJNR Am. J. Neuroradiol., May 1, 2007; 28(5): 864 - 869. [Abstract] [Full Text] [PDF]
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 Y. M. Ruigrok, G. J.E. Rinkel, R. van't Slot, M. Wolfs, S. Tang, and C. Wijmenga Evidence in favor of the contribution of genes involved in the maintenance of the extracellular matrix of the arterial wall to the development of intracranial aneurysms Hum. Mol. Genet., November 15, 2006; 15(22): 3361 - 3368. [Abstract] [Full Text] [PDF]
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 A. Slowik, A. Borratynska, W. Turaj, J. Pera, T. Dziedzic, D. A. Figlewicz, M. Betlej, T. Krzyszkowski, R. Czepko, and A. Szczudlik {alpha}1-Antichymotrypsin Gene (SERPINA3) A/T Polymorphism as a Risk Factor for Aneurysmal Subarachnoid Hemorrhage Stroke, April 1, 2005; 36(4): 737 - 740. [Abstract] [Full Text] [PDF]
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W. L. Young and G.-Y. Yang Are There Genetic Influences on Sporadic Brain Arteriovenous Malformations? Stroke, November 1, 2004; 35(11_suppl_1): 2740 - 2745. [Abstract] [Full Text] [PDF]
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 N. Katsuragi, R. Morishita, N. Nakamura, T. Ochiai, Y. Taniyama, Y. Hasegawa, K. Kawashima, Y. Kaneda, T. Ogihara, and K. Sugimura Periostin as a Novel Factor Responsible for Ventricular Dilation Circulation, September 28, 2004; 110(13): 1806 - 1813. [Abstract] [Full Text] [PDF]
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 R. A. Brekken, M. M. Sullivan, G. Workman, A. D. Bradshaw, J. Carbon, A. Siadak, C. Murri, P. E. Framson, and E. H. Sage Expression and Characterization of Murine Hevin (SC1), a Member of the SPARC Family of Matricellular Proteins J. Histochem. Cytochem., June 1, 2004; 52(6): 735 - 748. [Abstract] [Full Text] [PDF]
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T. Yoneyama, H. Kasuya, H. Onda, H. Akagawa, K. Hashiguchi, T. Nakajima, T. Hori, and I. Inoue Collagen Type I {alpha}2 (COL1A2) Is the Susceptible Gene for Intracranial Aneurysms Stroke, February 1, 2004; 35(2): 443 - 448. [Abstract] [Full Text] [PDF]
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D. Krex, H. Rohl, I. R. Konig, A. Ziegler, H. K. Schackert, and G. Schackert Tissue Inhibitor of Metalloproteinases-1, -2, and -3 Polymorphisms in a White Population With Intracranial Aneurysms Stroke, December 1, 2003; 34(12): 2817 - 2821. [Abstract] [Full Text] [PDF]
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A. Hofer, M. Hermans, N. Kubassek, M. Sitzer, H. Funke, F. Stogbauer, V. Ivaskevicius, J. Oldenburg, J. Burtscher, U. Knopp, et al. Elastin Polymorphism Haplotype and Intracranial Aneurysms Are Not Associated in Central Europe Stroke, May 1, 2003; 34(5): 1207 - 1211. [Abstract] [Full Text] [PDF]
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P. Lasjaunias and P. Porter Re: Molecular Anatomy of an Intracranial Aneurysm Stroke, November 1, 2001; 32 (11): 2725 - 2726. [Full Text] [PDF]
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