Biology of Intracranial Aneurysms: Role of Inflammation

Abstract

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.

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

“…Well-established regional differences in SMC phenotype at the molecular level have been documented and previously little was known about SMC differentiation in the cerebral circulation. Although prior studies have found that cerebral vascular injury and ischemia may result in an inflammatory response 3,14 and accumulating evidence suggests SMC phenotypic modulation and inflammation may have a role in the pathogenesis of cerebral aneurysms, 8 potential mechanisms remain incompletely understood. The current study presents novel data demonstrating that TNF-a produces profound phenotypic modulation of cerebral SMCs characterized by decreased expression of SMC contractile genes and increased expression of pro-inflammatory, pro-matrix-remodeling genes in vitro and in vivo.…”

“…8 This phenotypic alteration is believed to be characterized by a decreased expression of contractile proteins and an increased expression of inflammatory mediators. Prior studies have found that in response to injury and ischemia, TNF-a and other proinflammatory mediators are upregulated in cerebral blood vessels.…”

“…Tumor necrosis factor-alpha is a potent inflammatory cytokine released by numerous inflammatory cells and its induction has been linked to many risk factors for aneurysm formation, including hemodynamic stress, hypertension, aging, gender, alcohol, and smoking. 1,8,37 Although there have been limited studies, TNF-a has been found to be overexpressed in human aneurysms. 9 The most likely link is a combination of genetic, environmental, and hemodynamic factors that result in vascular injury and inflammation leading to TNF-a upregulation, vascular SMC phenotypic modulation and, ultimately, vessel wall degradation.…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…[7] There is a continuous balance between hemodynamic stress and the integrity of the vessel wall. [5] Upon the hemodynamic insult, this balance is perturbed, leading to vessel wall weakening. Dilation results, as extracellular matrix is degraded by increased levels of matrix metalloproteinases (MMP) compounded by concomitant apoptotic death of vascular smooth muscle cells (VSMCs).…”

“…The majority of evidence from intensive investigation has implicated a mounting inflammatory response during the aneurysm pathogenesis. [5,6] This data ultimately provides promising targets for in vivo molecular imaging and noninvasive IA therapeutics. This article will discuss inflammation as it pertains to IA pathogenesis, with a focus on the most recent investigation.…”