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.

Figure 1

Vascular smooth muscle cells (VSMCs) in intracranial aneurysm (IA) wall. Phenotypic modulation of VSMC from a contractile to pro-inflammatory/pro-matrix remodeling phenotype within the aneurysm wall leads to myointimal hyperplasia, inflammation, and vessel wall degeneration. Subsequent apoptosis and VSMC death lead to a hypocellular thin wall with increased IA susceptibility to rupture. SM-MHC, smooth muscle-myosin heavy chain; SM-α-actin, smooth muscle-α-actin; SSAO, semicarbazide-sensitive amine oxidase; NO, nitric oxide; TNFα, tumor necrosis factor-α; MCP1, monocyte chemoattractant protein 1; IL1β, Interleukin 1β; ROS, reactive oxygen species; MMPs, matrix metalloproteinases.

Figure 2

Inflammatory reaction associated with intracranial aneurysm (IA) formation. Aneurysm formation begins with a hemodynamically triggered endothelial dysfunction, followed by a mounting inflammatory response (implicating several inflammatory cells and mediators) and phenotypic modulation of VSMC from a contractile to pro-inflammatory/pro-matrix remodeling phenotype. The inflammatory response in vessel wall leads to disruption of IEL, extracellular matrix remodeling, and subsequent aneurysm formation. Further cell death and vessel wall degeneration ultimately culminate in IA rupture. VSMC, vascular smooth muscle cell; NF-κB, nuclear factor-κB; MCP1, monocyte chemoattractant protein 1; ECM, extracellular matrix; IEL, internal elastic lamina; IL, interleukin; TNFα, tumor necrosis factor-α; MMPs, matrix metalloproteinases; PGE2, prostaglandin E2; bFGF, basic fibroblast growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; TLR4, Toll like receptor-4; ROS, reactive oxygen species; Ig, immunoglobulin; SMC, smooth muscle cell; NO, nitric oxide.