Biology of intracranial aneurysms: role of inflammation

Keywords: aneurysms, endothelial cell, inflammation, intracranial, smooth muscle cell

Atherosclerosis is a Common Pathological Feature in Saccular Intracranial Aneurysms

Loss or disruption of the internal elastic lamina (IEL) is a characteristic feature of all IA. Indeed, in animal models, disruption of the IEL defines early aneurysm formation or early aneurysmal change (Fukuda et al, 2000; Hazama and Hashimoto, 1987; Kim et al, 1993; Morimoto et al, 2002; Nagata et al, 1980; Sadamasa et al, 2003). Beyond disruption of the IEL, another common feature of saccular IA is atherosclerotic change within the aneurysm wall. Killer-Oberpfalzer et al (2011) and Kosierkiewicz et al (1994) found that atherosclerotic lesions were present in all saccular IA. In the smallest aneurysms, diffuse intimal thickening (proliferating smooth muscle cells (SMCs)) and macrophages/lymphocytes are seen. In the largest aneurysms, advanced atherosclerotic lesions are found with phenotypically modulated SMCs, lipid-laden macrophages, and lymphocytes (Kosierkiewicz et al, 1994). Additionally, progression of atherosclerosis correlated positively with aneurysmal growth (Kosierkiewicz et al, 1994). Atherosclerosis appears to contribute to abdominal aortic aneurysm development as well (Dobrin, 1989; Nordon et al, 2009; Reed et al, 1992; Xu et al, 2001), which further supports the association between atherosclerosis and aneurysm formation in general. The two pathologies also share similar risk factors including smoking and arterial hypertension. Atherosclerosis is a disorder in which chronic inflammation is a critical pathogenic feature (Ait-Oufella et al, 2011; Andersson et al, 2010; Lahoute et al, 2011; Libby et al, 2010; Packard and Libby, 2008; Packard et al, 2009; Tedgui and Mallat, 2006). The possible association of IA with atherosclerosis and the critical role of inflammation in the pathogenesis of atherosclerosis could provide a common link between IA and inflammation. We hypothesize that pathogenic mechanisms underlying atherosclerosis also fundamentally underlie IA formation, progression, and rupture and this will be developed in further detail below.

Changes in Constituents of the Cerebral Blood Vessel Wall in Association with Intacranial Aneurysms

Perturbations of homeostasis in the cerebral blood vessel wall ultimately contribute to IA development and progression. In general, the highly organized structure of the cerebral blood vessel wall is transformed into a disorganized array with fewer distinct layers within the aneurysm wall. As mentioned, there is a striking loss or fragmentation of the internal IEL. Other histopathological features include irregularity of the luminal surface within the aneurysm sac, intimal hyperplasia, loss of cellular components, and disorganization of muscle fiber structure (Abruzzo et al, 1998; Draghia et al, 2008; Kataoka et al, 1999; Santiago-Sim and Kim, 2011; Scanarini et al, 1978; Schlote and Gaus, 1994). As a consequence of vascular remodeling, other changes in composition of the vessel wall have been noted including collagen content and extracellular matrix components. In the aneurysm, type I collagen and fibronectin appear dispersed throughout the wall in stark contrast to normal vessel wall where expression of type I collagen is restricted to the adventitia and fibronectin to the media (Austin et al, 1993). Furthermore, expression of type III and IV collagen and laminin appears to be decreased in aneurysm wall compared with normal vessels (Kilic et al, 2005).

The Common Pathway

The common pathway for aneurysm formation involves endothelial dysfunction/injury, a mounting inflammatory response, VSMC phenotypic modulation, extracellular matrix remodeling, and subsequent cell death and vessel wall degeneration. Endothelial dysfunction initially and vascular remodeling subsequently are triggered by shear stress (Sho et al, 2002). This explains why IA is commonly found at arterial junctions, bifurcations or abrupt vascular angles where excessive hemodynamic stresses are exerted on arterial walls (Kondo et al, 1997). There is a close relation between wall sheer stress, endothelial dysfunction, and the downstream inflammatory reaction (Nixon et al, 2010). In fact, the activity of the inflammatory transcription factor NF-κB is intimately modulated by the magnitude of shear stress exerted on vessel walls (Mohan et al, 1997). Hemodynamic stress was also found to alter the expression of several other genes that contribute to IA formation including MMP and TIMP (tissue inhibitors of MMPs) in a spatially localized manner within the aneurysm wall (Kadirvel et al, 2007). Along these lines, Wang et al (2009) showed in canine models that in areas of high shear stress (arterial bifurcations), aneurysm wall remodeling is associated with interleukin 1β (IL1β) and MMP expression along with a loss of endothelial nitric oxide synthase expression. In line with these findings, endothelial cell injury was found by Jamous et al (2005a, 2007) to be the earliest change in aneurysm wall, followed by the formation of an inflammatory zone that leads to proteolytic destruction of the vascular extracellular matrix by MMP and ultimately to aneurysm formation. This disturbance in arterial homeostasis was elegantly illustrated by Kassam et al (2004) in a study that compared the expression of several molecules in samples from aneurysm domes and extracranial arteries. The ability to express proteins specific to flow modulation (prostacyclin-stimulating factor) and arterial repair (RAI) as well as the extracellular matrix (type III collagen) was found to be impaired within the ruptured domes when compared with control superficial temporal artery (STA) tissue. There was also a graded loss of expression of these molecules from different samples which was, according to the authors, suggestive of a continuum from aneurysm formation to rupture. As discussed above, phenotypic modulation of VSMC with subsequent cell death is also an integral part of the inflammatory reaction that leads to aneurysm formation and vessel wall degeneration.

Matrix metalloproteinases appear to be robustly produced by both leukocytes (such as macrophages; Aoki et al, 2007a) and VSMC (Aoki et al, 2007b; Ishibashi et al, 2010; Kolega et al, 2011) within the vessel/aneurysm wall. The MMP digests arterial wall extracellular matrix and causes further damage via upregulation of other proteinases and angiogenic factors (Tronc et al, 2000). Overexpression of MMP 9 in the wall of excised IA was first documented by Kim et al (1997) followed by Takemura et al (2010) who later showed via immunohistochemical staining the overexpression of MMP 1, 2, and 9 in aneurysm walls. Moreover, the levels of MMP 2 and 9 were found to be higher in ruptured compared with unruptured aneurysms in a series of 30 patients, suggesting that excessive breakdown of vessel extracellular matrix eventually leads to rupture (Jin et al, 2007). In their pioneering work on experimentally induced aneurysms in animal models, Aoki et al (2007a, 2008c) showed the overexpression of MMP 2, 9 and cysteine cathepsins (another type of proteinases) in aneurysm wall. Inhibitors of either MMP (Aoki et al, 2007a) or cathepsins (Aoki et al, 2008c) successfully blocked the progression of IA highlighting the crucial role of these collagenases in the pathogenesis of IA. In line with their previous findings, aneurysm progression was promoted in mice after knocking out TIMP (Aoki et al, 2007b).

Collectively, these data show that the common pathway for aneurysm formation begins with a hemodynamically induced endothelial dysfunction followed by the development of an inflammatory reaction and VSMC phenotypic modulation in the arterial wall that ultimately leads to the breakdown of extracellular matrix by various proteinases and eventual cell death (Table 1; Figure 2; Supplementary Figure 2).

Leukocytes

The infiltration of inflammatory cells in general, and macrophages in particular, is a hallmark of IA (Chyatte et al, 1999; Frosen et al, 2004; Kataoka et al, 1999). Macrophages are thought to be the key factor in flow-induced vascular remodeling through the release of MMP (Nuki et al, 2009; Ota et al, 2009). In a recent well designed study by Kanematsu et al (2011), macrophage-depleted mice were found to have a substantially lower risk of developing IA compared with control mice (10% versus 60%, respectively). In addition, two studies have investigated the role of monocyte chemoattractant protein 1 (MCP1), a seemingly important chemoattractant of macrophages in atherosclerosis and abdominal aortic aneurysms (Egashira, 2003; Ishibashi et al, 2004), reporting a lower incidence of IA and inflammatory findings in MCP1-knockout mice (Aoki et al, 2009b; Kanematsu et al, 2011). MCP1 expression in VSMC of IA was found to be mediated by Ets-1, a transcription factor involved in several vascular inflammatory pathways (Aoki et al, 2010). Another key regulator of macrophage activation and recruitment is NF-κB. This transcription factor also specifically modulates the expression of several pro-inflammatory genes directly involved in aneurysm formation such as MMP, MCP1, and cytokines (Aoki and Nishimura, 2011). In a study by Aoki et al (2007c), NF-κB was overexpressed in walls of IA in rats and the formation of aneurysms was dramatically blocked after inhibition of NF-κB. The authors even hypothesized that the first step in IA formation is the activation of NF-κB in endothelial cells pursuant to hemodynamic stress (Aoki et al, 2007c). Aoki et al (2011a) extended their previous findings by showing that treating rats with chimeric decoy oligodeoxynucleotides that simultaneously inhibited NF-κB and Ets-1 1 month after aneurysm induction surgery decreased aneurysm size and thickened aneurysm walls of preexisting aneurysms. Furthermore, this treatment reduced expression of MCP1, macrophage infiltration and restored collagen biosynthesis in aneurysm walls (Aoki et al, 2011a). The role of MCP1, Ets-1, and NF-κB seems therefore pivotal in recruiting macrophages into the wall of IA, initiating the inflammatory reaction and contributing to aneurysm formation and progression.

Macrophages are not the only cells involved in the inflammatory reaction in the wall of IA. As previously noted, the endothelial cell is thought to be the initiator of the events. T cells also actively participate alongside macrophages in the inflammatory reaction (Chyatte et al, 1999; Frosen et al, 2004). In fact, infiltration of the vessel wall by macrophages and T cells associates with aneurysm rupture as reported by Frosen et al (2004) in a study that histologically compared 42 ruptured with 24 unruptured IAs. Furthermore, macrophage infiltration was associated with VSMC proliferation in the aneurysm wall. Based on these data, the authors hypothesized that macrophages may induce phenotypic modulation (and proliferation) in VSMC. Leukocyte infiltration and VSMC proliferation were seen in aneurysm samples resected <12 hours after rupture. It is unclear whether these changes were present before rupture or were simply a response to aneurysm rupture.

Mast cells are leukocytes involved in various inflammatory conditions such as allergy that act mainly through the release of mediators and cytokines (Krishnaswamy et al, 2006). Their role in the pathogenesis of atherosclerosis and abdominal aortic aneurysms has been well defined (Mayranpaa et al, 2009; Tang et al, 2009). Recently, Ishibashi et al (2010) assessed the role of these cells in IA formation using an experimental rat model. They found an increased number of mast cells during the formation of IA and an induction of MMP in VSMC after mast cell degranulation. Progression of IA was also halted after administration of a mast cell degranulation inhibitor through the blockade of different components of the inflammatory response. Based on the results of this study, it seems that mast cells constitute an integral part of the inflammatory response that leads to IA formation.

Complement and Immunoglobulins

Complement and Ig have also been studied as possible contributors to the pathogenesis of IA. Their presence in the walls of IA has been reported in human and animal studies (Aoki and Nishimura, 2011; Chyatte et al, 1999). The distinguished work of the Helsinki group from Finland has pointed to the importance of C in the pathogenesis of rupture of IA. In one study that compared ruptured with unruptured IA, the expression of membrane attack complex (C activation end product) was greater in ruptured samples and associated significantly with aneurysm wall degeneration and inflammatory cell infiltration (Tulamo et al, 2006). Later, the same group showed that activation of C occurs via the classical pathway as evidenced by the presence of classical pathway activators (IgG, IgM, C-reactive protein, oxidized low-density lipoprotein) in the IA wall (Tulamo et al, 2010a). In a recently published paper, they showed that in contrast to the luminal part, the outer wall of IA lacked C inhibitors and was subject to full-blown C activation (Tulamo et al, 2010b). However, the authors failed to provide a reasonable explanation as to how C activation can lead to cell wall degeneration and ultimately rupture of IA. These data favor a substantial role for C in the pathogenesis of IA progression and rupture. However, the need for further investigation of this facet of the inflammatory response is apparent.

Cytokines, Growth Factors, and Other Mediators

Cytokines are a heterogeneous group of soluble short acting proteins and peptides that are powerful mediators of the immune and inflammatory response (Ait-Oufella et al, 2011; Sprague and Khalil, 2009; Tedgui and Mallat, 2006). Several cytokines have been found to be involved in the pathogenesis of IA especially IL1β, IL6, and tumor necrosis factor-α (TNFα). The IL1β may be produced by monocytes, macrophages, T and B cells, dendritic cells, endothelial cells, and VSMC (Sprague and Khalil, 2009). The IL1β is induced in the early stages of IA formation in mice and prominently localizes to VSMC (Moriwaki et al, 2006). Its presence promotes VSMC apoptosis (Moriwaki et al, 2006). The IL1β−/− mice were compared with age-matched wild-type mice. Although no difference was detected in the rate of aneurysm development between IL1β−/− and wild-type mice, there were significantly fewer advanced aneurysms seen in IL1β−/− mice. Moreover, apoptosis was significantly reduced in aneurysms in IL1β−/− compared with wild-type animals (Moriwaki et al, 2006). Collectively, these data suggest that IL1β is important in aneurysm progression (Moriwaki et al, 2006).

Case–control studies using allelic-association models have provided indirect evidence for a potential role of IL6 in IA pathogenesis. Specifically, IL6 gene polymorphisms were shown to be associated with IA. The 572C/174G haplotype and the GG genotype predisposed to IA in a British (Morgan et al, 2006) and Chinese (Sun et al, 2008) population, respectively. More recently, Zhang et al (2011) showed an association of IL6-572G/C gene polymorphisms with IA in a Cantonese population, suggesting that the IL6-572G/C gene is an important candidate gene for IA. To overcome issues related to sample size and variability of results, McColgan et al (2010) conducted a meta-analysis based on all available published data. They found that the IL6 gene G572C polymorphism associated with IA (odds ratio 7.08, 95% confidence interval 2.85 to 17.57). Interestingly, the IL6/G174C polymorphism was associated with a significant protective effect against IA (odds ratio 0.49, 95% confidence interval 0.25 to 0.95). Taken together, it appears that IL6 is a candidate gene that contributes to IA pathogenesis. Further investigation into this association, however, is required to define the role of IL6 in IA biology.

Tumor necrosis factor-α is a potent pro-inflammatory cytokine that is also an inductive signal in initiation of apoptosis (Ait-Oufella et al, 2011; Jayaraman et al, 2005, 2008; Sprague and Khalil, 2009; Tedgui and Mallat, 2006). In addition, TNFα is known to activate MMP (Polavarapu et al, 2005; Thomson et al, 2012), which is critical in aneurysm pathology. Risk factors associated with aneurysm development have been associated with TNFα induction (Jayaraman et al, 2008), including hypertension (Munoz et al, 1999), hemodynamic flow (Gonzalez et al, 1992; Hoi et al, 2004; Jou et al, 2005; Kapadia et al, 2000), aging (Hartel et al, 2005; Kirwan et al, 2001; Paolisso et al, 1998), gender (Ferreri, 2007; Huang et al, 2005), alcohol (Lanzke et al, 2007; Luedemann et al, 2005), and smoking (Anto et al, 2002; Sun et al, 2007; Wright et al, 2007). In a study by Jayaraman et al (2005), the expression of TNFα and its proapoptotic downstream target FAS were increased in IA, indicating that TNFα has a proapoptotic and pro-inflammatory action in the wall of aneurysms. Building on this prior work, Jayaraman et al (2008) report that elevated TNFα in human IA correlates with increased expression of intracellular calcium release channels that regulate intracellular calcium, Toll like receptors that mediate innate immunity and a reduction in expression of TIMP-1. Further indirect support of a role for TNFα in aneurysm pathogenesis includes association of TNFα gene polymorphisms with IA (Fontanella et al, 2007; Low et al, 2011). In summary, data suggest that TNFα may be an important factor in IA pathogenesis but additional investigation is necessary to more clearly elucidate its role.

A variety of growth factors may have a basic role in aneurysm formation and rupture through wall remodeling. Receptors for vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor β were found to be associated with the inflammatory reaction and the remodeling process in the walls of IA (Frosen et al, 2006). A decrease in the levels of transforming growth factor α may also contribute to aneurysm formation although the mechanisms involved remain speculative (Kilic et al, 2005).

Angiotensin II is a potent vasoconstrictor, a mediator of atherosclerosis, and a potent pro-inflammatory stimulant (MacKenzie, 2011; Montecucco et al, 2009). A potential role of angiotensin II in IA, however, has not been clearly elucidated. Angiotensin II has an important role in aortic aneurysms. Based on this premise, Aoki et al (2009d) examined a role for angiotensin II in a rodent model of IA. They found that angiotensin type I receptor was not upregulated and subcutaneous administration of an angiotensin type I receptor antagonist did not inhibit inflammation nor cerebral aneurysm formation (Aoki et al, 2009d). A recent review suggested that there is strong, albeit circumstantial, evidence for a relationship between the brain renin–angiotensin system and the pathogenesis of IA (Shoja et al, 2011). They emphasized the need for research focused on the association between polymorphisms in renin–angiotensin system-related genes and the incidence of IA (Shoja et al, 2011).

Recently, endothelial and neuronal nitric oxide synthase, two enzymes that generate nitric oxide, were shown to have a protective role against IA formation (Aoki et al, 2011b). This could be explained by the vasodilator action of nitric oxide that relieves hemodynamic stress and prevent the subsequent inflammatory reaction in vessel walls (thereby maintaining normal critical endothelial function).

Gene Expression Profile

Numerous studies have recently profiled gene expression in IA, using microarray or PCR techniques, in an attempt to characterize the pathogenesis of formation and rupture of these lesions. These studies are potentially powerful and informative but have limitations including the status of the sample aneurysm (ruptured versus symptomatic unruptured versus asymptomatic unruptured, timing of harvest versus onset of rupture, location, etc.), the tissue used for control (extracranial versus intracranial vessel, small versus large vessel, etc.), the size of the cohort examined, and the techniques used for analysis. Not surprisingly, the results of these studies are heterogeneous and leave considerable room for future investigation (Table 2).

In an early preliminary study by Peters et al (2001), the authors compared a single aneurysm from a 3-year-old girl with control STA using a global gene expression analysis approach (SAGE-Lite). They found overexpression of genes encoding extracellular matrix components, genes involved in extracellular matrix turnover, cell adhesion and antiadhesion, cytokinesis, and cell migration. Upon careful inspection, the authors found changes in expression of messenger ribonucleic acid involved with inflammation and immune response including major histocompatibility complex class I and II markers and Ig. It is unclear whether a single aneurysm in a 3-year-old patient can be generalized to IA in the general population. As an extension of this prior work, this same group examined changes in expression of genes between aneurysm domes and control STA or occipital artery vessels in a much larger cohort (Kassam et al, 2004). However, this study only focused on select genes concerned with flow modulation and arterial repair identified in the aforementioned preliminary study and did not examine inflammatory genes.

Next, Krischek et al (2008) conducted a networked-based gene expression analysis of IA tissue using oligonucleotide microarrays. They examined six ruptured and four unruptured aneurysms and compared these with control intracranial arteries (obtained from feeding arteries to arteriovenous malformations at the time of craniotomy). This use of an intracranial vessel as a control (even though it was on a feeding vessel to an arteriovenous malformation) is a strength as extracranial vessels (which are easier to obtain) were used in previous work and may not be representative control vessels. They found 521 differentially expressed genes. The two most significantly associated gene ontology terms were antigen processing and immune response. Upon further analysis, the most significant canonical pathways involved in aneurysm tissue included antigen presentation, integrin signaling, chemokine signaling, C and coagulation cascades, nitric oxide signaling in the cardiovascular system, and IL10 signaling. Real-time RT-PCR provided confirmation of these results. The authors provided strong evidence for major histocompatibility complex class II gene overexpression in human IA tissue and concluded that antigen-presenting cells (macrophages and monocytes) have a key role in IA formation.

Kadirvel et al (2008) conducted a gene expression analysis of experimental saccular aneurysms using deoxyribonucleic acid microarrays in their established rabbit elastase model. They found that multiple genes in diverse pathways were differentially expressed in the rabbit aneurysm model. Inflammation-related genes were not found to be upregulated. It is important to note that inflammation is rarely observed in this model. In addition, only 209 genes were examined using this custom-made rabbit microarray (which is a limited repertoire of genes examined compared with current microarrays in other species).

Aoki et al (2008a) conducted an interesting experiment where they examined a gene expression profile of the intima and media in an experimental rodent model of IA using laser-captured microdissection technique and microarray analysis. The microarray used examined 41,012 genes. They showed that 633 genes were differentially expressed between normal cerebral artery and cerebral aneurysm in the intima (395 showing increased and 238 showing decreased expression). In the media, 1,344 genes were differentially expressed (with 928 showing increased and 416 showing decreased expression). Further analysis of genes that showed increased expression indicated that these genes were involved in pathways concerned with proteinases, reactive oxygen species, growth factor, chemokine, C, adhesion molecules, and apoptosis in both the intima and media of aneurysmal walls. Additionally, some genes showed an opposite expression pattern in the intima versus media suggesting a different role between endothelial cells and VSMC in the process. The authors concluded that IA formation and progression appears to be closely related to vascular inflammation, degeneration of extracellular matrix, and apoptosis.

Li et al (2009) conducted a transcriptome-wide characterization of gene expression associated with unruptured IA. They examined three unruptured aneurysms and compared these with STA control tissue. They found that 1,160 genes were differentially expressed (164 were upregulated and 996 were downregulated). Extracellular matrix-related genes and MMP were significantly upregulated. However, in contrast to prior reports, a number of immune/inflammation-related genes were found to be downregulated in IA. The authors suggested that the observed downregulation of many immune/inflammation-related genes may be due to differences in aneurysm samples compared with prior studies (unruptured aneurysms in this case compared with ruptured aneurysms in others). Furthermore, the authors suggest that inflammation may be a response to hemorrhage rather than a contributor. An alternative explanation may be that inflammation leads to rupture (previous authors show that the inflammatory response is present shortly after rupture (Frosen et al, 2004) and not simply a response to rupture). Again, this study examined only three aneurysm samples and the control was the extracranial STA.

Shi et al (2009) conducted Illumina microarray analysis on human IA via comparison of aneurysm wall and STA tissue from six consecutive patients (three ruptured and three unruptured lesions). They found that 326 genes were differentially expressed between IA and STA (>2-fold change with a false discovery rate <0.01). The authors found differentially expressed genes involved focal adhesion, extracellular matrix receptor interaction, cell communication, inflammatory response, and apoptosis. This study was limited by its small sample size and use of STA as control tissue. However, they conducted a careful statistical analysis using stringent criteria to denote significance.

Marchese et al (2010) conducted another deoxyribonucleic acid microarray analysis of gene expression in aneurysm walls versus control (STA or middle meningeal) arteries. They included both ruptured and unruptured aneurysms. In ruptured aneurysms, genes showing differential expression included structural proteins of the extracellular matrix, members of the MMP family and genes involved with apoptosis. When comparing ruptured with unruptured aneurysms, TIMP-3 was seen to be markedly downregulated and inducible nitric oxide synthase was significantly overexpressed. The authors conclude that the inhibitor of MMP, the pathway of nitric oxide, and the apoptotic process have an important role in weakening of the vessel wall that can result in formation and rupture of IA. Changes in specific inflammation-related genes were not emphasized.

In a well-designed microarray study, Pera et al (2010) examined transcription profiles in ruptured (n=6) and unruptured (n=4) IA compared with control middle meningeal arteries. There were changes in expression of 159 genes compared with control with 131 genes showing common directions of change in both ruptured and unruptured IA. They found consistent downregulation of genes involved with the muscle system and cell adhesion with upregulation of genes involved with the immune system and inflammatory response. Interestingly, the expression of genes related to the immune system and inflammation was found to be reduced in ruptured compared with unruptured aneurysms, suggesting a protective role of inflammation against rupture. This latter observation leaves the role of inflammation unclear; the authors suggest that inflammation may participate in the healing process within IA protecting against IA rupture. Limitations such as the limited number of samples, the use of the noncerebral middle meningeal vessel, and a potential discrepancy in baseline risk factors (including high incidence of hypertension in patients with unruptured aneurysms) should be noted.

In a recent study, Kurki et al (2011) compared gene expression patterns in 11 ruptured and 8 unruptured IA using oligonucleotide microarrays. A total of 686 genes were found to be significantly upregulated and 740 were downregulated in ruptured IA. Upregulated pathways included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling, and extracellular matrix degradation. Significantly enriched genes were Toll like receptor, NF-κB, hypoxia-inducible factor-1A, and Ets transcription factor binding sites. These data add to the growing body of evidence, suggesting that the biology of ruptured IA is distinct from that of unruptured IA, with inflammation being a key factor in the pathway leading to IA rupture. Among the limitations of this study are the specific ethnicity of the studied population (genetically homogeneous Finnish population) and the small sample size (though larger than previous studies). Additionally, it is hard to conclude confidently based on the results of this study that inflammation was the cause rather than the consequence of aneurysm rupture. The findings of this study are in line with those of previous studies comparing ruptured and unruptured aneurysms. Kataoka et al (1999) compared histologically 44 ruptured with 27 unruptured aneurysms and found that ruptured aneurysms manifested significantly more endothelial damage, structural changes, and inflammatory cell invasion compared with unruptured aneurysms. There was also a significant correlation between the degree of inflammatory cell invasion and the level of fragility of the wall. Importantly, the time from rupture to resection did not show any correlation with the degree of inflammation, which indicates that the inflammatory response was probably present before IA rupture (since an acute inflammatory response would be expected to change over time). Along similar lines, Frosen et al (2004) compared histologically 42 ruptured with 24 unruptured IA and noted that apoptosis, deendothelialization, luminal thrombosis, SMC proliferation, and T-cell/macrophage infiltration associated with IA rupture. Collectively, these studies indicate that the pathobiology of ruptured aneurysms could be substantially different from that of unruptured aneurysms which potentially explains why only a minority of IA progresses to rupture.

Overall, it appears that alterations in expression of immune system and inflammation-related genes are frequently observed in IA from human and experimental models and highlight their importance in the pathogenesis of IA formation, progression, and rupture. Differences in technique of ribonucleic acid harvest/extraction, microarray used, statistical analysis, type of aneurysm studied, and type of control vessel used may explain the heterogeneous results across studies.

Table 3. Targeted therapies for intracranial aneurysms (IAs).

Supplementary Figure 1

Supplementary Figure 2

Supplementary Figures Legends

1. Abruzzo T, Shengelaia GG, Dawson RC, 3rd, Owens DS, Cawley CM, Gravanis MB. Histologic and morphologic comparison of experimental aneurysms with human intracranial aneurysms. AJNR Am J Neuroradiol. 1998;19:1309–1314. [PMC free article] [PubMed] [Google Scholar]
2. Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31:969–979. doi: 10.1161/ATVBAHA.110.207415. [DOI] [PubMed] [Google Scholar]
3. Andersson J, Libby P, Hansson GK. Adaptive immunity and atherosclerosis. Clin Immunol. 2010;134:33–46. doi: 10.1016/j.clim.2009.07.002. [DOI] [PubMed] [Google Scholar]
4. Anto RJ, Mukhopadhyay A, Shishodia S, Gairola CG, Aggarwal BB. Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2. Carcinogenesis. 2002;23:1511–1518. doi: 10.1093/carcin/23.9.1511. [DOI] [PubMed] [Google Scholar]
5. Aoki T, Kataoka H, Ishibashi R, Nakagami H, Nozaki K, Morishita R, Hashimoto N.2009aPitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor kappaB pathway Neurosurgery 64357–365.discussion 365–6 [DOI] [PubMed] [Google Scholar]
6. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Egashira K, Hashimoto N. Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke. 2009b;40:942–951. doi: 10.1161/STROKEAHA.108.532556. [DOI] [PubMed] [Google Scholar]
7. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Gene expression profile of the intima and media of experimentally induced cerebral aneurysms in rats by laser-microdissection and microarray techniques. Int J Mol Med. 2008a;22:595–603. [PubMed] [Google Scholar]
8. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats. Stroke. 2008b;39:1276–1285. doi: 10.1161/STROKEAHA.107.503086. [DOI] [PubMed] [Google Scholar]
9. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Cathepsin B, K, and S are expressed in cerebral aneurysms and promote the progression of cerebral aneurysms. Stroke. 2008c;39:2603–2610. doi: 10.1161/STROKEAHA.107.513648. [DOI] [PubMed] [Google Scholar]
10. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Morishita R, Hashimoto N. Reduced collagen biosynthesis is the hallmark of cerebral aneurysm: contribution of interleukin-1beta and nuclear factor-kappaB. Arterioscler Thromb Vasc Biol. 2009c;29:1080–1086. doi: 10.1161/ATVBAHA.108.180760. [DOI] [PubMed] [Google Scholar]
11. Aoki T, Kataoka H, Morimoto M, Nozaki K, Hashimoto N. Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats. Stroke. 2007a;38:162–169. doi: 10.1161/01.STR.0000252129.18605.c8. [DOI] [PubMed] [Google Scholar]
12. Aoki T, Kataoka H, Moriwaki T, Nozaki K, Hashimoto N. Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke. 2007b;38:2337–2345. doi: 10.1161/STROKEAHA.107.481838. [DOI] [PubMed] [Google Scholar]
13. Aoki T, Kataoka H, Nishimura M, Ishibashi R, Morishita R, Miyamoto S. Ets-1 promotes the progression of cerebral aneurysm by inducing the expression of MCP-1 in vascular smooth muscle cells. Gene Therapy. 2010;17:1117–1123. doi: 10.1038/gt.2010.60. [DOI] [PubMed] [Google Scholar]
14. Aoki T, Kataoka H, Nishimura M, Ishibashi R, Morishita R, Miyamoto S. Regression of intracranial aneurysms by simultaneous inhibition of NF-kappaB and Ets with chimeric decoy oligodeoxynucleotide treatment. Neurosurgery. 2011a;70:1534–1543. doi: 10.1227/NEU.0b013e318246a390. [DOI] [PubMed] [Google Scholar]
15. Aoki T, Kataoka H, Shimamura M, Nakagami H, Wakayama K, Moriwaki T, Ishibashi R, Nozaki K, Morishita R, Hashimoto N. NF-kappaB is a key mediator of cerebral aneurysm formation. Circulation. 2007c;116:2830–2840. doi: 10.1161/CIRCULATIONAHA.107.728303. [DOI] [PubMed] [Google Scholar]
16. Aoki T, Nishimura M. The development and the use of experimental animal models to study the underlying mechanisms of CA formation. J Biomed Biotechnol. 2011;2011:535921. doi: 10.1155/2011/535921. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Aoki T, Nishimura M, Kataoka H, Ishibashi R, Miyake T, Takagi Y, Morishita R, Hashimoto N. Role of angiotensin II type 1 receptor in cerebral aneurysm formation in rats. Int J Mol Med. 2009d;24:353–359. doi: 10.3892/ijmm_00000239. [DOI] [PubMed] [Google Scholar]
18. Aoki T, Nishimura M, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Reactive oxygen species modulate growth of cerebral aneurysms: a study using the free radical scavenger edaravone and p47phox(−/−) mice. Lab Invest. 2009e;89:730–741. doi: 10.1038/labinvest.2009.36. [DOI] [PubMed] [Google Scholar]
19. Aoki T, Nishimura M, Kataoka H, Ishibashi R, Nozaki K, Miyamoto S. Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS. Lab Invest. 2011b;91:619–626. doi: 10.1038/labinvest.2010.204. [DOI] [PubMed] [Google Scholar]
20. Aoki T, Nishimura M, Matsuoka T, Yamamoto K, Furuyashiki T, Kataoka H, Kitaoka S, Ishibashi R, Ishibazawa A, Miyamoto S, Morishita R, Ando J, Hashimoto N, Nozaki K, Narumiya S. PGE(2) -EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-kappaB. Br J Pharmacol. 2011c;163:1237–1249. doi: 10.1111/j.1476-5381.2011.01358.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Austin G, Fisher S, Dickson D, Anderson D, Richardson S. The significance of the extracellular matrix in intracranial aneurysms. Ann Clin Lab Sci. 1993;23:97–105. [PubMed] [Google Scholar]
22. Bilguvar K, Yasuno K, Niemela M, Ruigrok YM, von Und Zu Fraunberg M, van Duijn CM, van den Berg LH, Mane S, Mason CE, Choi M, Gaal E, Bayri Y, Kolb L, Arlier Z, Ravuri S, Ronkainen A, Tajima A, Laakso A, Hata A, Kasuya H, Koivisto T, Rinne J, Ohman J, Breteler MM, Wijmenga C, State MW, Rinkel GJ, Hernesniemi J, Jaaskelainen JE, Palotie A, Inoue I, Lifton RP, Gunel M. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet. 2008;40:1472–1477. doi: 10.1038/ng.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Bygglin H, Laaksamo E, Myllarniemi M, Tulamo R, Hernesniemi J, Niemela M, Laakso A. Isolation, culture, and characterization of smooth muscle cells from human intracranial aneurysms. Acta Neurochir. 2011;153:311–318. doi: 10.1007/s00701-010-0836-x. [DOI] [PubMed] [Google Scholar]
24. Chyatte D, Bruno G, Desai S, Todor DR.1999Inflammation and intracranial aneurysms Neurosurgery 451137–1146.discussion 1146–7 [DOI] [PubMed] [Google Scholar]
25. Dobrin PB. Pathophysiology and pathogenesis of aortic aneurysms. Current concepts. Surg Clin North Am. 1989;69:687–703. doi: 10.1016/s0039-6109(16)44876-0. [DOI] [PubMed] [Google Scholar]
26. Draghia F, Draghia AC, Onicescu D. Electron microscopic study of the arterial wall in the cerebral aneurysms. Rom J Morphol Embryol. 2008;49:101–103. [PubMed] [Google Scholar]
27. Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF, Kassell NF, Lee KS.2003aCerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation Neurosurgery 53123–133.discussion 133–5 [DOI] [PubMed] [Google Scholar]
28. Dumont AS, Dumont RJ, McNeill JH, Kassell NF, Sutherland GR, Verma S.2003bChronic endothelin antagonism restores cerebrovascular function in diabetes Neurosurgery 52653–660.discussion 659–60 [DOI] [PubMed] [Google Scholar]
29. Dumont AS, Hyndman ME, Dumont RJ, Fedak PM, Kassell NF, Sutherland GR, Verma S. Improvement of endothelial function in insulin-resistant carotid arteries treated with pravastatin. J Neurosurg. 2001a;95:466–471. doi: 10.3171/jns.2001.95.3.0466. [DOI] [PubMed] [Google Scholar]
30. Dumont AS, Lovren F, McNeill JH, Sutherland GR, Triggle CR, Anderson TJ, Verma S. Augmentation of endothelial function by endothelin antagonism in human saphenous vein conduits. J Neurosurg. 2001b;94:281–286. doi: 10.3171/jns.2001.94.2.0281. [DOI] [PubMed] [Google Scholar]
31. Egashira K. Molecular mechanisms mediating inflammation in vascular disease: special reference to monocyte chemoattractant protein-1. Hypertension. 2003;41:834–841. doi: 10.1161/01.HYP.0000051642.65283.36. [DOI] [PubMed] [Google Scholar]
32. Ferreri NR. Estrogen-TNF interactions and vascular inflammation. Am J Physiol Heart Circ Physiol. 2007;292:H2566–H2569. doi: 10.1152/ajpheart.00193.2007. [DOI] [PubMed] [Google Scholar]
33. Fontanella M, Rainero I, Gallone S, Rubino E, Fenoglio P, Valfre W, Garbossa D, Carlino C, Ducati A, Pinessi L.2007Tumor necrosis factor-alpha gene and cerebral aneurysms Neurosurgery 60668–672.discussion 672–3 [DOI] [PubMed] [Google Scholar]
34. Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke. 2004;35:2287–2293. doi: 10.1161/01.STR.0000140636.30204.da. [DOI] [PubMed] [Google Scholar]
35. Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J.2006Growth factor receptor expression and remodeling of saccular cerebral artery aneurysm walls: implications for biological therapy preventing rupture Neurosurgery 58534–541.discussion 534–41 [DOI] [PubMed] [Google Scholar]
36. Fukuda S, Hashimoto N, Naritomi H, Nagata I, Nozaki K, Kondo S, Kurino M, Kikuchi H. Prevention of rat cerebral aneurysm formation by inhibition of nitric oxide synthase. Circulation. 2000;101:2532–2538. doi: 10.1161/01.cir.101.21.2532. [DOI] [PubMed] [Google Scholar]
37. Gonzalez CF, Cho YI, Ortega HV, Moret J. Intracranial aneurysms: flow analysis of their origin and progression. AJNR Am J Neuroradiol. 1992;13:181–188. [PMC free article] [PubMed] [Google Scholar]
38. Guo F, Li Z, Song L, Han T, Feng Q, Guo Y, Xu J, He M, You C. Increased apoptosis and cysteinyl aspartate specific protease-3 gene expression in human intracranial aneurysm. J Clin Neurosci. 2007;14:550–555. doi: 10.1016/j.jocn.2005.11.018. [DOI] [PubMed] [Google Scholar]
39. Hartel C, Adam N, Strunk T, Temming P, Muller-Steinhardt M, Schultz C. Cytokine responses correlate differentially with age in infancy and early childhood. Clin Exp Immunol. 2005;142:446–453. doi: 10.1111/j.1365-2249.2005.02928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Hasan DM, Mahaney KB, Brown RD, Jr, Meissner I, Piepgras DG, Huston J, Capuano AW, Torner JC. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke. 2011;42:3156–3162. doi: 10.1161/STROKEAHA.111.619411. [DOI] [PMC free article] [PubMed] [Google Scholar]
41. Hashimoto T, Meng H, Young WL. Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol Res. 2006;28:372–380. doi: 10.1179/016164106X14973. [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Hazama F, Hashimoto N. An animal model of cerebral aneurysms. Neuropathol Appl Neurobiol. 1987;13:77–90. doi: 10.1111/j.1365-2990.1987.tb00173.x. [DOI] [PubMed] [Google Scholar]
43. Hoi Y, Meng H, Woodward SH, Bendok BR, Hanel RA, Guterman LR, Hopkins LN. Effects of arterial geometry on aneurysm growth: three-dimensional computational fluid dynamics study. J Neurosurg. 2004;101:676–681. doi: 10.3171/jns.2004.101.4.0676. [DOI] [PubMed] [Google Scholar]
44. Huang Y, Cao S, Nagamani M, Anderson KE, Grady JJ, Lu LJ. Decreased circulating levels of tumor necrosis factor-alpha in postmenopausal women during consumption of soy-containing isoflavones. J Clin Endocrinol Metab. 2005;90:3956–3962. doi: 10.1210/jc.2005-0161. [DOI] [PubMed] [Google Scholar]
45. Ishibashi M, Egashira K, Zhao Q, Hiasa K, Ohtani K, Ihara Y, Charo IF, Kura S, Tsuzuki T, Takeshita A, Sunagawa K. Bone marrow-derived monocyte chemoattractant protein-1 receptor CCR2 is critical in angiotensin II-induced acceleration of atherosclerosis and aneurysm formation in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol. 2004;24:e174–e178. doi: 10.1161/01.ATV.0000143384.69170.2d. [DOI] [PubMed] [Google Scholar]
46. Ishibashi R, Aoki T, Nishimura M, Hashimoto N, Miyamoto S. Contribution of mast cells to cerebral aneurysm formation. Curr Neurovasc Res. 2010;7:113–124. doi: 10.2174/156720210791184916. [DOI] [PubMed] [Google Scholar]
47. ISUIA Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. International Study of Unruptured Intracranial Aneurysms Investigators. N Engl J Med. 1998;339:1725–1733. doi: 10.1056/NEJM199812103392401. [DOI] [PubMed] [Google Scholar]
48. Jamous MA, Nagahiro S, Kitazato KT, Satoh K, Satomi J. Vascular corrosion casts mirroring early morphological changes that lead to the formation of saccular cerebral aneurysm: an experimental study in rats. J Neurosurg. 2005a;102:532–535. doi: 10.3171/jns.2005.102.3.0532. [DOI] [PubMed] [Google Scholar]
49. Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Aziz HA, Shono M, Satoh K. Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats. J Neurosurg. 2007;107:405–411. doi: 10.3171/JNS-07/08/0405. [DOI] [PubMed] [Google Scholar]
50. Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Kuwayama K, Satoh K. Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part II: experimental study of the effects of hormone replacement therapy in rats. J Neurosurg. 2005b;103:1052–1057. doi: 10.3171/jns.2005.103.6.1052. [DOI] [PubMed] [Google Scholar]
51. Jayaraman T, Berenstein V, Li X, Mayer J, Silane M, Shin YS, Niimi Y, Kilic T, Gunel M, Berenstein A.2005Tumor necrosis factor alpha is a key modulator of inflammation in cerebral aneurysms Neurosurgery 57558–564.discussion 558-64 [DOI] [PubMed] [Google Scholar]
52. Jayaraman T, Paget A, Shin YS, Li X, Mayer J, Chaudhry H, Niimi Y, Silane M, Berenstein A. TNF-alpha-mediated inflammation in cerebral aneurysms: a potential link to growth and rupture. Vasc Health Risk Manag. 2008;4:805–817. doi: 10.2147/vhrm.s2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
53. Jin D, Sheng J, Yang X, Gao B.2007Matrix metalloproteinases and tissue inhibitors of metalloproteinases expression in human cerebral ruptured and unruptured aneurysm Surg Neurol 68(Suppl 2S11–S16.discussion S6 [DOI] [PubMed] [Google Scholar]
54. Jou LD, Wong G, Dispensa B, Lawton MT, Higashida RT, Young WL, Saloner D. Correlation between lumenal geometry changes and hemodynamics in fusiform intracranial aneurysms. AJNR Am J Neuroradiol. 2005;26:2357–2363. [PMC free article] [PubMed] [Google Scholar]
55. Juvela S. Prevalence of and risk factors for intracranial aneurysms. Lancet Neurol. 2011;10:595–597. doi: 10.1016/S1474-4422(11)70125-9. [DOI] [PubMed] [Google Scholar]
56. Kadirvel R, Ding YH, Dai D, Lewis DA, Raghavakaimal S, Cloft HJ, Kallmes DF. Gene expression profiling of experimental saccular aneurysms using deoxyribonucleic acid microarrays. AJNR Am J Neuroradiol. 2008;29:1566–1569. doi: 10.3174/ajnr.A1125. [DOI] [PMC free article] [PubMed] [Google Scholar]
57. Kadirvel R, Ding YH, Dai D, Zakaria H, Robertson AM, Danielson MA, Lewis DA, Cloft HJ, Kallmes DF. The influence of hemodynamic forces on biomarkers in the walls of elastase-induced aneurysms in rabbits. Neuroradiology. 2007;49:1041–1053. doi: 10.1007/s00234-007-0295-0. [DOI] [PubMed] [Google Scholar]
58. Kanematsu Y, Kanematsu M, Kurihara C, Tada Y, Tsou TL, van Rooijen N, Lawton MT, Young WL, Liang EI, Nuki Y, Hashimoto T. Critical roles of macrophages in the formation of intracranial aneurysm. Stroke. 2011;42:173–178. doi: 10.1161/STROKEAHA.110.590976. [DOI] [PMC free article] [PubMed] [Google Scholar]
59. Kapadia SR, Yakoob K, Nader S, Thomas JD, Mann DL, Griffin BP. Elevated circulating levels of serum tumor necrosis factor-alpha in patients with hemodynamically significant pressure and volume overload. J Am Coll Cardiol. 2000;36:208–212. doi: 10.1016/s0735-1097(00)00721-x. [DOI] [PubMed] [Google Scholar]
60. Kassam AB, Horowitz M, Chang YF, Peters D.2004Altered arterial homeostasis and cerebral aneurysms: a molecular epidemiology study Neurosurgery 541450–1460.discussion 1460–2 [DOI] [PubMed] [Google Scholar]
61. Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R. Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke. 1999;30:1396–1401. doi: 10.1161/01.str.30.7.1396. [DOI] [PubMed] [Google Scholar]
62. Kilic T, Sohrabifar M, Kurtkaya O, Yildirim O, Elmaci I, Gunel M, Pamir MN.2005Expression of structural proteins and angiogenic factors in normal arterial and unruptured and ruptured aneurysm walls Neurosurgery 57997–1007.discussion 997–1007 [DOI] [PubMed] [Google Scholar]
63. Killer-Oberpfalzer M, Aichholzer M, Weis S, Richling B, Jones R, Virmani R, Cruise GM.2011Histological analysis of clipped human intracranial aneurysms and parent arteries with short-term follow-up Cardiovasc Pathol(in press) [DOI] [PubMed]
64. Kim C, Cervos-Navarro J, Kikuchi H, Hashimoto N, Hazama F. Degenerative changes in the internal elastic lamina relating to the development of saccular cerebral aneurysms in rats. Acta Neurochir. 1993;121:76–81. doi: 10.1007/BF01405187. [DOI] [PubMed] [Google Scholar]
65. Kim SC, Singh M, Huang J, Prestigiacomo CJ, Winfree CJ, Solomon RA, Connolly ES., Jr1997Matrix metalloproteinase-9 in cerebral aneurysms Neurosurgery 41642–666.discussion 646–7 [DOI] [PubMed] [Google Scholar]
66. Kimura N, Shimizu H, Eldawoody H, Nakayama T, Saito A, Tominaga T, Takahashi A. Effect of olmesartan and pravastatin on experimental cerebral aneurysms in rats. Brain Res. 2010;1322:144–152. doi: 10.1016/j.brainres.2010.01.044. [DOI] [PubMed] [Google Scholar]
67. Kirwan JP, Krishnan RK, Weaver JA, Del Aguila LF, Evans WJ. Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia. Am J Physiol Endocrinol Metab. 2001;281:E1137–E1143. doi: 10.1152/ajpendo.2001.281.6.E1137. [DOI] [PubMed] [Google Scholar]
68. Kolega J, Gao L, Mandelbaum M, Mocco J, Siddiqui AH, Natarajan SK, Meng H. Cellular and molecular responses of the basilar terminus to hemodynamics during intracranial aneurysm initiation in a rabbit model. J Vasc Res. 2011;48:429–442. doi: 10.1159/000324840. [DOI] [PMC free article] [PubMed] [Google Scholar]
69. Kondo S, Hashimoto N, Kikuchi H, Hazama F, Nagata I, Kataoka H.1997Cerebral aneurysms arising at nonbranching sites. An experimental Study Stroke 28398–403.discussion 403–4 [DOI] [PubMed] [Google Scholar]
70. Kondo S, Hashimoto N, Kikuchi H, Hazama F, Nagata I, Kataoka H.1998Apoptosis of medial smooth muscle cells in the development of saccular cerebral aneurysms in rats Stroke 29181–188.discussion 189 [DOI] [PubMed] [Google Scholar]
71. Kosierkiewicz TA, Factor SM, Dickson DW. Immunocytochemical studies of atherosclerotic lesions of cerebral berry aneurysms. J Neuropathol Exp Neurol. 1994;53:399–406. doi: 10.1097/00005072-199407000-00012. [DOI] [PubMed] [Google Scholar]
72. Krischek B, Kasuya H, Tajima A, Akagawa H, Sasaki T, Yoneyama T, Ujiie H, Kubo O, Bonin M, Takakura K, Hori T, Inoue I. Network-based gene expression analysis of intracranial aneurysm tissue reveals role of antigen presenting cells. Neuroscience. 2008;154:1398–1407. doi: 10.1016/j.neuroscience.2008.04.049. [DOI] [PubMed] [Google Scholar]
73. Krishnaswamy G, Ajitawi O, Chi DS. The human mast cell: an overview. Methods Mol Biol. 2006;315:13–34. doi: 10.1385/1-59259-967-2:013. [DOI] [PubMed] [Google Scholar]
74. Kurki MI, Hakkinen SK, Frosen J, Tulamo R, von und zu Fraunberg M, Wong G, Tromp G, Niemela M, Hernesniemi J, Jaaskelainen JE, Yla-Herttuala S.2011Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: an emerging regulative role of Toll-like receptor signaling and nuclear factor-kappaB, hypoxia-inducible factor-1A, and ETS transcription factors Neurosurgery 681667–1675.discussion 75–6 [DOI] [PubMed] [Google Scholar]
75. Lahoute C, Herbin O, Mallat Z, Tedgui A. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol. 2011;8:348–358. doi: 10.1038/nrcardio.2011.62. [DOI] [PubMed] [Google Scholar]
76. Lanzke N, Kleinwachter R, Kerschischnik S, Sargsyan L, Groneberg DA, Kamradt T, Liesenfeld O, Krenn V, Sander M, Spies C. Differential effects of ethanol on IFN-gamma- and TNF-alpha-producing splenic T lymphocytes in a murine model of gram-negative pneumonia. Addict Biol. 2007;12:59–68. doi: 10.1111/j.1369-1600.2006.00042.x. [DOI] [PubMed] [Google Scholar]
77. Li L, Yang X, Jiang F, Dusting GJ, Wu Z. Transcriptome-wide characterization of gene expression associated with unruptured intracranial aneurysms. Eur Neurol. 2009;62:330–337. doi: 10.1159/000236911. [DOI] [PubMed] [Google Scholar]
78. Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circ J. 2010;74:213–220. doi: 10.1253/circj.cj-09-0706. [DOI] [PubMed] [Google Scholar]
79. Low SK, Zembutsu H, Takahashi A, Kamatani N, Cha PC, Hosono N, Kubo M, Matsuda K, Nakamura Y. Impact of LIMK1, MMP2 and TNF-alpha variations for intracranial aneurysm in Japanese population. J Hum Genet. 2011;56:211–216. doi: 10.1038/jhg.2010.169. [DOI] [PubMed] [Google Scholar]
80. Luedemann C, Bord E, Qin G, Zhu Y, Goukassian D, Losordo DW, Kishore R. Ethanol modulation of TNF-alpha biosynthesis and signaling in endothelial cells: synergistic augmentation of TNF-alpha mediated endothelial cell dysfunctions by chronic ethanol. Alcohol Clin Exp Res. 2005;29:930–938. doi: 10.1097/01.alc.0000171037.90100.6b. [DOI] [PubMed] [Google Scholar]
81. MacKenzie A. Endothelium-derived vasoactive agents, AT1 receptors and inflammation. Pharmacol Ther. 2011;131:187–203. doi: 10.1016/j.pharmthera.2010.11.001. [DOI] [PubMed] [Google Scholar]
82. Marbacher S, Schlappi JA, Fung C, Husler J, Beck J, Raabe A. Do statins reduce the risk of aneurysm development: a case-control study. J Neurosurg. 2011;116:638–642. doi: 10.3171/2011.10.JNS11153. [DOI] [PubMed] [Google Scholar]
83. Marchese E, Vignati A, Albanese A, Nucci CG, Sabatino G, Tirpakova B, Lofrese G, Zelano G, Maira G. Comparative evaluation of genome-wide gene expression profiles in ruptured and unruptured human intracranial aneurysms. J Biol Regul Homeost Agents. 2010;24:185–195. [PubMed] [Google Scholar]
84. Mayranpaa MI, Trosien JA, Fontaine V, Folkesson M, Kazi M, Eriksson P, Swedenborg J, Hedin U.2009Mast cells associate with neovessels in the media and adventitia of abdominal aortic aneurysms J Vasc Surg 50388–395.discussion 395–6 [DOI] [PubMed] [Google Scholar]
85. McColgan P, Thant KZ, Sharma P. The genetics of sporadic ruptured and unruptured intracranial aneurysms: a genetic meta-analysis of 8 genes and 13 polymorphisms in approximately 20,000 individuals. J Neurosurg. 2010;112:714–721. doi: 10.3171/2009.8.JNS092. [DOI] [PubMed] [Google Scholar]
86. Meng H, Metaxa E, Gao L, Liaw N, Natarajan SK, Swartz DD, Siddiqui AH, Kolega J, Mocco J. Progressive aneurysm development following hemodynamic insult. J Neurosurg. 2011;114:1095–1103. doi: 10.3171/2010.9.JNS10368. [DOI] [PubMed] [Google Scholar]
87. Meng H, Wang Z, Hoi Y, Gao L, Metaxa E, Swartz DD, Kolega J. Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation. Stroke. 2007;38:1924–1931. doi: 10.1161/STROKEAHA.106.481234. [DOI] [PMC free article] [PubMed] [Google Scholar]
88. Merei FT, Gallyas F. Role of the structural elements of the arterial wall in the formation and growth of intracranial saccular aneurysms. Neurol Res. 1980;2:283–303. doi: 10.1080/01616412.1980.11739584. [DOI] [PubMed] [Google Scholar]
89. Mohan S, Mohan N, Sprague EA. Differential activation of NF-kappa B in human aortic endothelial cells conditioned to specific flow environments. Am J Physiol. 1997;273:C572–C578. doi: 10.1152/ajpcell.1997.273.2.C572. [DOI] [PubMed] [Google Scholar]
90. Montecucco F, Pende A, Mach F. The renin-angiotensin system modulates inflammatory processes in atherosclerosis: evidence from basic research and clinical studies. Mediators Inflamm. 2009;2009:752406. doi: 10.1155/2009/752406. [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Morgan L, Cooper J, Montgomery H, Kitchen N, Humphries SE. The interleukin-6 gene -174G>C and -572G>C promoter polymorphisms are related to cerebral aneurysms. J Neurol Neurosurg Psychiatry. 2006;77:915–917. doi: 10.1136/jnnp.2005.081976. [DOI] [PMC free article] [PubMed] [Google Scholar]
92. Morimoto M, Miyamoto S, Mizoguchi A, Kume N, Kita T, Hashimoto N. Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes. Stroke. 2002;33:1911–1915. doi: 10.1161/01.str.0000021000.19637.3d. [DOI] [PubMed] [Google Scholar]
93. Moriwaki T, Takagi Y, Sadamasa N, Aoki T, Nozaki K, Hashimoto N. Impaired progression of cerebral aneurysms in interleukin-1beta-deficient mice. Stroke. 2006;37:900–905. doi: 10.1161/01.STR.0000204028.39783.d9. [DOI] [PubMed] [Google Scholar]
94. Munoz J, Albillos A, Perez-Paramo M, Rossi I, Alvarez-Mon M. Factors mediating the hemodynamic effects of tumor necrosis factor-alpha in portal hypertensive rats. Am J Physiol. 1999;276:G687–G693. doi: 10.1152/ajpgi.1999.276.3.G687. [DOI] [PubMed] [Google Scholar]
95. Nagata I, Handa H, Hashimoto N, Hazama F. Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension. Surg Neurol. 1980;14:477–479. [PubMed] [Google Scholar]
96. Nagata I, Handa H, Hasimoto N, Hazama F. Experimentally induced cerebral aneurysms in rats: VII. Scanning electron microscope study. Surg Neurol. 1981;16:291–296. doi: 10.1016/0090-3019(81)90063-x. [DOI] [PubMed] [Google Scholar]
97. Nakajima N, Nagahiro S, Sano T, Satomi J, Satoh K. Phenotypic modulation of smooth muscle cells in human cerebral aneurysmal walls. Acta Neuropathol. 2000;100:475–480. doi: 10.1007/s004010000220. [DOI] [PubMed] [Google Scholar]
98. Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009;8:635–642. doi: 10.1016/S1474-4422(09)70126-7. [DOI] [PubMed] [Google Scholar]
99. Nixon AM, Gunel M, Sumpio BE. The critical role of hemodynamics in the development of cerebral vascular disease. J Neurosurg. 2010;112:1240–1253. doi: 10.3171/2009.10.JNS09759. [DOI] [PubMed] [Google Scholar]
100. Nordon IM, Hinchliffe RJ, Holt PJ, Loftus IM, Thompson MM. Review of current theories for abdominal aortic aneurysm pathogenesis. Vascular. 2009;17:253–263. doi: 10.2310/6670.2009.00046. [DOI] [PubMed] [Google Scholar]
101. Nuki Y, Matsumoto MM, Tsang E, Young WL, van Rooijen N, Kurihara C, Hashimoto T. Roles of macrophages in flow-induced outward vascular remodeling. J Cereb Blood Flow Metab. 2009;29:495–503. doi: 10.1038/jcbfm.2008.136. [DOI] [PMC free article] [PubMed] [Google Scholar]
102. Ota R, Kurihara C, Tsou TL, Young WL, Yeghiazarians Y, Chang M, Mobashery S, Sakamoto A, Hashimoto T. Roles of matrix metalloproteinases in flow-induced outward vascular remodeling. J Cereb Blood Flow Metab. 2009;29:1547–1558. doi: 10.1038/jcbfm.2009.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
103. Owens GK. Molecular control of vascular smooth muscle cell differentiation. Acta Physiol Scand. 1998;164:623–635. doi: 10.1111/j.1365-201x.1998.tb10706.x. [DOI] [PubMed] [Google Scholar]
104. Owens GK.2007Molecular control of vascular smooth muscle cell differentiation and phenotypic plasticity Novartis Found Symp 283174–191.discussion 191–3, 238–41 [DOI] [PubMed] [Google Scholar]
105. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004;84:767–801. doi: 10.1152/physrev.00041.2003. [DOI] [PubMed] [Google Scholar]
106. Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008;54:24–38. doi: 10.1373/clinchem.2007.097360. [DOI] [PubMed] [Google Scholar]
107. Packard RR, Lichtman AH, Libby P. Innate and adaptive immunity in atherosclerosis. Semin Immunopathol. 2009;31:5–22. doi: 10.1007/s00281-009-0153-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
108. Paolisso G, Rizzo MR, Mazziotti G, Tagliamonte MR, Gambardella A, Rotondi M, Carella C, Giugliano D, Varricchio M, D'Onofrio F. Advancing age and insulin resistance: role of plasma tumor necrosis factor-alpha. Am J Physiol. 1998;275:E294–E299. doi: 10.1152/ajpendo.1998.275.2.E294. [DOI] [PubMed] [Google Scholar]
109. Pera J, Korostynski M, Krzyszkowski T, Czopek J, Slowik A, Dziedzic T, Piechota M, Stachura K, Moskala M, Przewlocki R, Szczudlik A. Gene expression profiles in human ruptured and unruptured intracranial aneurysms: what is the role of inflammation. Stroke. 2010;41:224–231. doi: 10.1161/STROKEAHA.109.562009. [DOI] [PubMed] [Google Scholar]
110. Peters DG, Kassam AB, Feingold E, Heidrich-O'Hare E, Yonas H, Ferrell RE, Brufsky A. Molecular anatomy of an intracranial aneurysm: coordinated expression of genes involved in wound healing and tissue remodeling. Stroke. 2001;32:1036–1042. doi: 10.1161/01.str.32.4.1036. [DOI] [PubMed] [Google Scholar]
111. Polavarapu R, Gongora MC, Winkles JA, Yepes M. Tumor necrosis factor-like weak inducer of apoptosis increases the permeability of the neurovascular unit through nuclear factor-kappa B pathway activation. J Neurosci. 2005;25:10094–10100. doi: 10.1523/JNEUROSCI.3382-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
112. Reed D, Reed C, Stemmermann G, Hayashi T. Are aortic aneurysms caused by atherosclerosis. Circulation. 1992;85:205–211. doi: 10.1161/01.cir.85.1.205. [DOI] [PubMed] [Google Scholar]
113. Sadamasa N, Nozaki K, Hashimoto N. Disruption of gene for inducible nitric oxide synthase reduces progression of cerebral aneurysms. Stroke. 2003;34:2980–2984. doi: 10.1161/01.STR.0000102556.55600.3B. [DOI] [PubMed] [Google Scholar]
114. Sadamasa N, Nozaki K, Takagi Y, Moriwaki T, Kawanabe Y, Ishikawa M, Hashimoto N. Cerebral aneurysm progression suppressed by blockage of endothelin B receptor. J Neurosurg. 2007;106:330–336. doi: 10.3171/jns.2007.106.2.330. [DOI] [PubMed] [Google Scholar]
115. Sakaki T, Kohmura E, Kishiguchi T, Yuguchi T, Yamashita T, Hayakawa T.1997Loss and apoptosis of smooth muscle cells in intracranial aneurysms. Studies with in situ DNA end labeling and antibody against single-stranded DNA Acta Neurochir 139469–474.discussion 74–5 [DOI] [PubMed] [Google Scholar]
116. Sakamoto N, Saito N, Han X, Ohashi T, Sato M. Effect of spatial gradient in fluid shear stress on morphological changes in endothelial cells in response to flow. Biochem Biophys Res Commun. 2010;395:264–269. doi: 10.1016/j.bbrc.2010.04.002. [DOI] [PubMed] [Google Scholar]
117. Santiago-Sim T, Kim DH.2011Pathobiology of intracranial aneurysms Youmans Neurological Surgery(Winn HR, ed), 6th ed.Vol. 4Philadelphia, PA: Elsevier, Saunders; 3747–3755. [Google Scholar]
118. Scanarini M, Mingrino S, Giordano R, Baroni A. Histological and ultrastructural study of intracranial saccular aneurysmal wall. Acta Neurochir. 1978;43:171–182. doi: 10.1007/BF01587953. [DOI] [PubMed] [Google Scholar]
119. Schlote W, Gaus C. Histologic aspects from ruptured and nonruptured aneurysms. Neurol Res. 1994;16:59–62. doi: 10.1080/01616412.1994.11740194. [DOI] [PubMed] [Google Scholar]
120. Shi C, Awad IA, Jafari N, Lin S, Du P, Hage ZA, Shenkar R, Getch CC, Bredel M, Batjer HH, Bendok BR. Genomics of human intracranial aneurysm wall. Stroke. 2009;40:1252–1261. doi: 10.1161/STROKEAHA.108.532036. [DOI] [PubMed] [Google Scholar]
121. Sho E, Sho M, Singh TM, Nanjo H, Komatsu M, Xu C, Masuda H, Zarins CK. Arterial enlargement in response to high flow requires early expression of matrix metalloproteinases to degrade extracellular matrix. Exp Mol Pathol. 2002;73:142–153. doi: 10.1006/exmp.2002.2457. [DOI] [PubMed] [Google Scholar]
122. Shoja MM, Agutter PS, Tubbs RS, Payner TD, Ghabili K, Cohen-Gadol AA. The role of the renin–angiotensin system in the pathogenesis of intracranial aneurysms. J Renin Angiotensin Aldosterone Syst. 2011;12:262–273. doi: 10.1177/1470320310387845. [DOI] [PubMed] [Google Scholar]
123. Sibon I, Mercier N, Darret D, Lacolley P, Lamaziere JM. Association between semicarbazide-sensitive amine oxidase, a regulator of the glucose transporter, and elastic lamellae thinning during experimental cerebral aneurysm development: laboratory investigation. J Neurosurg. 2008;108:558–566. doi: 10.3171/JNS/2008/108/3/0558. [DOI] [PubMed] [Google Scholar]
124. Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol. 2009;78:539–552. doi: 10.1016/j.bcp.2009.04.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
125. Sun H, Zhang D, Zhao J. The interleukin-6 gene-572G>C promoter polymorphism is related to intracranial aneurysms in Chinese Han nationality. Neurosci Lett. 2008;440:1–3. doi: 10.1016/j.neulet.2008.04.077. [DOI] [PubMed] [Google Scholar]
126. Sun SH, Tang WX, Liu C, Lin H, Yang HH. [Effects of tumor necrosis factor alpha on proteolysis of respiratory muscles in rats with chronic obstructive pulmonary disease] Zhonghua Jie He He Hu Xi Za Zhi. 2007;30:186–191. [PubMed] [Google Scholar]
127. Szymanski MP, Metaxa E, Meng H, Kolega J. Endothelial cell layer subjected to impinging flow mimicking the apex of an arterial bifurcation. Ann Biomed Eng. 2008;36:1681–1689. doi: 10.1007/s10439-008-9540-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
128. Tada Y, Kitazato KT, Yagi K, Shimada K, Matsushita N, Kinouchi T, Kanematsu Y, Satomi J, Kageji T, Nagahiro S. Statins promote the growth of experimentally induced cerebral aneurysms in estrogen-deficient rats. Stroke. 2011;42:2286–2293. doi: 10.1161/STROKEAHA.110.608034. [DOI] [PubMed] [Google Scholar]
129. Tada Y, Yagi K, Kitazato KT, Tamura T, Kinouchi T, Shimada K, Matsushita N, Nakajima N, Satomi J, Kageji T, Nagahiro S. Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats. J Hypertens. 2010;28:1883–1891. doi: 10.1097/HJH;0b013e32833c2273. [DOI] [PubMed] [Google Scholar]
130. Takagi Y, Ishikawa M, Nozaki K, Yoshimura S, Hashimoto N.2002Increased expression of phosphorylated c-Jun amino-terminal kinase and phosphorylated c-Jun in human cerebral aneurysms: role of the c-Jun amino-terminal kinase/c-Jun pathway in apoptosis of vascular walls Neurosurgery 51997–1002.discussion 1002–4 [DOI] [PubMed] [Google Scholar]
131. Takemura Y, Hirata Y, Sakata N, Nabeshima K, Takeshita M, Inoue T. Histopathologic characteristics of a saccular aneurysm arising in the non-branching segment of the distal middle cerebral artery. Pathol Res Pract. 2010;206:391–396. doi: 10.1016/j.prp.2009.10.002. [DOI] [PubMed] [Google Scholar]
132. Tamura T, Jamous MA, Kitazato KT, Yagi K, Tada Y, Uno M, Nagahiro S. Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. J Hypertens. 2009;27:1284–1292. doi: 10.1097/HJH.0b013e328329d1a7. [DOI] [PubMed] [Google Scholar]
133. Tang YL, Yang YZ, Wang S, Huang T, Tang CK, Xu ZX, Sun YH. Mast cell degranulator compound 48-80 promotes atherosclerotic plaque in apolipoprotein E knockout mice with perivascular common carotid collar placement. Chin Med J (Engl) 2009;122:319–325. [PubMed] [Google Scholar]
134. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515–581. doi: 10.1152/physrev.00024.2005. [DOI] [PubMed] [Google Scholar]
135. Thomson EM, Williams A, Yauk CL, Vincent R. Overexpression of tumor necrosis factor-alpha in the lungs alters immune response, matrix remodeling, and repair and maintenance pathways. Am J Pathol. 2012;180:1413–1430. doi: 10.1016/j.ajpath.2011.12.020. [DOI] [PubMed] [Google Scholar]
136. Tronc F, Mallat Z, Lehoux S, Wassef M, Esposito B, Tedgui A. Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO. Arterioscler Thromb Vasc Biol. 2000;20:E120–E126. doi: 10.1161/01.atv.20.12.e120. [DOI] [PubMed] [Google Scholar]
137. Tulamo R, Frosen J, Junnikkala S, Paetau A, Pitkaniemi J, Kangasniemi M, Niemela M, Jaaskelainen J, Jokitalo E, Karatas A, Hernesniemi J, Meri S.2006Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture Neurosurgery 591069–1076.discussion 1076–7 [DOI] [PubMed] [Google Scholar]
138. Tulamo R, Frosen J, Junnikkala S, Paetau A, Kangasniemi M, Pelaez J, Hernesniemi J, Niemela M, Meri S. Complement system becomes activated by the classical pathway in intracranial aneurysm walls. Lab Invest. 2010a;90:168–179. doi: 10.1038/labinvest.2009.133. [DOI] [PubMed] [Google Scholar]
139. Tulamo R, Frosen J, Paetau A, Seitsonen S, Hernesniemi J, Niemela M, Jarvela I, Meri S. Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation. Am J Pathol. 2010b;177:3224–3232. doi: 10.2353/ajpath.2010.091172. [DOI] [PMC free article] [PubMed] [Google Scholar]
140. Wang Z, Kolega J, Hoi Y, Gao L, Swartz DD, Levy EI, Mocco J, Meng H.2009Molecular alterations associated with aneurysmal remodeling are localized in the high hemodynamic stress region of a created carotid bifurcation Neurosurgery 65169–177.discussion 177–8 [DOI] [PMC free article] [PubMed] [Google Scholar]
141. Wei H, Mao Q, Liu L, Xu Y, Chen J, Jiang R, Yin L, Fan Y, Chopp M, Dong J, Zhang J. Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm. J Neurosci Res. 2011;89:1822–1828. doi: 10.1002/jnr.22696. [DOI] [PubMed] [Google Scholar]
142. Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke. 2007;38:1404–1410. doi: 10.1161/01.STR.0000260955.51401.cd. [DOI] [PubMed] [Google Scholar]
143. Wiebers DO, Whisnant JP, Huston J, 3rd, Meissner I, Brown RD, Jr, Piepgras DG, Forbes GS, Thielen K, Nichols D, O'Fallon WM, Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362:103–110. doi: 10.1016/s0140-6736(03)13860-3. [DOI] [PubMed] [Google Scholar]
144. Wright JL, Tai H, Wang R, Wang X, Churg A. Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-alpha signaling. Am J Physiol. 2007;292:L125–L133. doi: 10.1152/ajplung.00539.2005. [DOI] [PubMed] [Google Scholar]
145. Xu C, Zarins CK, Glagov S. Aneurysmal and occlusive atherosclerosis of the human abdominal aorta. J Vasc Surg. 2001;33:91–96. doi: 10.1067/mva.2001.109744. [DOI] [PubMed] [Google Scholar]
146. Xu Y, Tian Y, Wei HJ, Chen J, Dong JF, Zacharek A, Zhang JN. Erythropoietin increases circulating endothelial progenitor cells and reduces the formation and progression of cerebral aneurysm in rats. Neuroscience. 2011;181:292–299. doi: 10.1016/j.neuroscience.2011.02.051. [DOI] [PubMed] [Google Scholar]
147. Yagi K, Tada Y, Kitazato KT, Tamura T, Satomi J, Nagahiro S.2010Ibudilast inhibits cerebral aneurysms by down-regulating inflammation-related molecules in the vascular wall of rats Neurosurgery 66551–559.discussion 559 [DOI] [PubMed] [Google Scholar]
148. Yoshida T, Owens GK. Molecular determinants of vascular smooth muscle cell diversity. Circ Res. 2005;96:280–291. doi: 10.1161/01.RES.0000155951.62152.2e. [DOI] [PubMed] [Google Scholar]
149. Zhang D, Zhao J, Sun Y, Wang S, Tai WH, Cochrane DD, Li J. Pathological observation of brain arteries and spontaneous aneurysms in hypertensive rats. Chin Med J (Engl) 2003;116:424–427. [PubMed] [Google Scholar]
150. Zhang G, Tu Y, Feng W, Huang L, Li M, Qi S. Association of interleukin-6-572G/C gene polymorphisms in the Cantonese population with intracranial aneurysms. J Neurol Sci. 2011;306:94–97. doi: 10.1016/j.jns.2011.03.036. [DOI] [PubMed] [Google Scholar]

Supplementary Materials