Biology of cerebral arteriovenous malformations with a focus on inflammation

Abstract

Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

Figure 1

Contributors to AVM pathogenesis. The SNPs shown above upregulate the inflammatory response to inciting events and lead to the overexpression of proinflammatory cytokines, which in turn exacerbate the inflammation, recruit leukocytes and activate the endothelial cells of the AVM. As a result, increased vascular damage and angiogenesis are observed, resulting in AVM formation and expansion. AVM, arteriovenous malformation; CAMs, cell adhesion molecules; EC, endothelial cell; ICAM-1, intercellular cell adhesion molecule-1; IL1RN, interleukin-1 receptor antagonist; IL-6, interleukin-6; IL-1α, interleukin-1-alpha; IL-1β, interleukin-1-beta; IL-8, interleukin-8; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinase; MPO, myeloperoxidase; SNPs, single-nucleotide polymorphisms; TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.