Apoptosis of Medial Smooth Muscle Cells in the Development of Saccular Cerebral Aneurysms in Rats

Kondo, Shunya; Hashimoto, Nobuo; Kikuchi, Hiroe; Hazama, Fumitada; Nagata, Izumi; Kataoka, Hideo

doi:10.1161/01.str.29.1.181

Cited by 150 publications

(92 citation statements)

References 30 publications

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“…28,30 The number of such apoptotic cells has been shown to correlate with the probability of rupture of cerebral aneurysms. 41,42 In addition to repression of SMC differentiation marker genes, KLF4 is a pluripotency factor involved in the reprogramming of somatic cells. 15 This may, in part, explain how inflammatory cells and cytokines promote vascular wall remodeling and aneurysm formation.…”

Section: Discussionmentioning

confidence: 99%

TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

Ali

Starke

Jabbour

et al. 2013

J Cereb Blood Flow Metab

136

107

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Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF-a) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-a-actin, SM-22a, smooth muscle myosin heavy chain), while dominant-negative cells suppressed expression. Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased expression of KLF4, a known regulator of SMC differentiation. Kruppel-like transcription factor 4 (KLF4) small interfering RNA abrogated TNF-a activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF-a and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF-a inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays in vivo and in vitro demonstrated that TNFa promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF-a induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF-a in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.

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Section: Discussionmentioning

confidence: 99%

TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

Ali

Starke

Jabbour

et al. 2013

J Cereb Blood Flow Metab

136

107

View full text Add to dashboard Cite

show abstract

“…Furthermore, collagen biosynthesis and processing was seen to be significantly inhibited in VSMC in an experimental aneurysm model (Aoki et al, 2009c). It appears that subsequent changes in the media layer include apoptosis/loss of VSMC, changes in VSMC proliferation, and thinning of the aneurysm wall (Frosen et al, 2004;Guo et al, 2007;Jayaraman et al, 2008;Kondo et al, 1998;Meng et al, 2007;Sadamasa et al, 2007;Sakaki et al, 1997;Takagi et al, 2002).…”

Section: Intracranial Aneurysms and Pathological Changes In Vascular mentioning

confidence: 99%

Biology of Intracranial Aneurysms: Role of Inflammation

Chalouhi

Ali

Jabbour

et al. 2012

J Cereb Blood Flow Metab

417

418

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Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

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“…5,15,28,32,33 Hashimoto and colleagues established an experimentally induced cerebral aneurysm model in rats, and hemodynamic stress has been emphasized for aneurysmal formation. In the early stage after aneurysm induction, disruption of the elastic laminae occurs, 22,24 which is followed by infiltration of the inflammatory-related mediator to the arterial wall, and proteolytic damage to the arterial wall caused by inflammation-related mediators appears to play a crucial role. Several kinds of mediators have been reported to be decisive causes of the formation of abdominal aortic aneurysms, 13,23 and Chyatte et al demonstrated the expression of immunoglobulin, macrophages, and T-lymphocytes in humans in the walls of unruptured cerebral aneurysms.…”

confidence: 99%

Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor–α inhibitor

Yokoi¹,

Isono

Saitoh³

et al. 2014

JNS

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Object Although cerebral aneurysmal subarachnoid hemorrhage is a devastating disease for humans, effective medical treatments have not yet been established. Recent reports have shown that regression of some inflammatory-related mediators has protective effects in experimental cerebral aneurysm models. This study corroborated the effectiveness of tumor necrosis factor–α (TNF-α) inhibitor for experimentally induced cerebral aneurysms in rats. Methods Five-week-old male rats were prepared for induction of cerebral aneurysms and divided into 3 groups, 2 groups administered different concentrations of a TNF-α inhibitor (etanercept), and 1 control group. One month after aneurysm induction, 7-T MRI was performed. The TNF-α inhibitor groups received subcutaneous injection of 25 μg or 2.5 μg of etanercept, and the control group received subcutaneous injection of normal saline every week. The TNF-α inhibitor administrations were started at 1 month after aneurysm induction to evaluate its suppressive effects on preexisting cerebral aneurysms. Arterial circles of Willis were obtained and evaluated 3 months after aneurysm induction. Results Rats administered a TNF-α inhibitor experienced significant increases in media thickness and reductions in aneurysmal size compared with the control group. Immunohistochemical staining showed that treatment with a TNF-α inhibitor suppressed matrix metalloproteinase (MMP)–9 and inducible nitric oxide synthase (iNOS) expression through the luminal surface of the endothelial cell layer, the media and the adventitia at the site of aneurysmal formation, and the anterior cerebral artery–olfactory artery bifurcation. Quantitative polymerase chain reaction also showed suppression of MMP-9 and iNOS by TNF-α inhibitor administration. Conclusions Therapeutic administration of a TNF-α inhibitor significantly reduced the formation of aneurysms in rats. These data also suggest that TNF-α suppression reduced some inflammatory-related mediators that are in the downstream pathway of nuclear factor-κB.

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Apoptosis of Medial Smooth Muscle Cells in the Development of Saccular Cerebral Aneurysms in Rats

Abstract: The present findings indicate that there is an association between apoptosis of medial SMCs and the formation of saccular cerebral aneurysms.

Cited by 150 publications

References 30 publications

TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

Biology of Intracranial Aneurysms: Role of Inflammation

Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor–α inhibitor

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