Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor κB (NF-κB), and inflammatory signaling involving prostaglandin E (PGE) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-κB activation during intracranial aneurysm development in mice showed that NF-κB was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an IκBα mutant that restricts NF-κB activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-κB activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-α (TNF-α) to activate NF-κB and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.

Background and Purpose Saccular intracranial aneurysm (sIA) is a common disease that may cause devastating intracranial hemorrhage. Hemodynamics, wall remodeling, and wall inflammation have been associated with sIA rupture. We investigated how sIA hemodynamics associates with wall remodeling and inflammation of the sIA wall. Methods Tissue samples resected during sIA surgery (11 unruptured, 9 ruptured sIAs) were studied with histology and immunohistochemistry. Patient-specific computational models of hemodynamics were created from preoperative CT-angiographies. Results More stable and less complex flows were associated with thick, hyperplastic sIA walls while slower flows with more diffuse inflow were associated with degenerated and decellularized sIA walls. Wall degeneration (p=0.041) and rupture was associated with increased inflammation (CD45+, p=0.031). High wall shear stress (WSS, p=0.018), higher vorticity (VO, p=0.046), higher viscous dissipation (VD, p=0.046), and high shear rate (SR, p=0.046) associated with increased inflammation. Inflammation was also associated with lack of intact endothelium (p=0.034), and presence of organized luminal thrombosis (p=0.018), although overall organized thrombosis was associated with low minimum WSS (p=0.034) and not with the flow conditions that associated with inflammation. Conclusions Flow conditions in the sIA associate with wall remodeling. Inflammation, which is associated with degenerative wall remodeling and rupture, is associated with high flow activity including elevated WSS. Endothelial injury may be a mechanism by which flow induces inflammation in the sIA wall. Hemodynamic simulations might prove to be useful in identifying sIAs at risk of developing inflammation, a potential biomarker for rupture.

Chronic inflammation contributes to remodeling, degeneration, and rupture of saccular intracranial artery aneurysms. Mast cells are important proinflammatory and proangiogenic cells in chronic inflammatory vascular diseases. Here we studied mast cells and neovascularization in 36 intraoperatively resected aneurysms using histology and immunohistochemistry and analyzed the clinical characteristics of the aneurysms according to bleeding status (unruptured vs ruptured). Among the 36 aneurysms, 9 contained mast cells (tryptase-positive cells) and 15 contained neovessels (CD34- and CD31-positive capillarylike structures). The density of neovessels was significantly higher in aneurysm walls containing mast cells than in walls not containing them. In particular, wall areas with abundant mast cells and neovessels also contained iron deposits, indicating damage of newly formed endothelium with ensuing microhemorrhages. Walls with the highest neovessel density and the greatest iron deposition also showed evidence of degeneration. Finally, none of the mast cell-containing aneurysms showed an intact luminal endothelium. Thus, mast cells may adversely affect both neovascular and luminal endothelia. The novel association of mast cells with neovessels and injurious microhemorrhages, as well as with luminal endothelial erosion, suggests that mast cells contribute to remodeling and degeneration of saccular intracranial artery aneurysms.

Saccular intracranial aneurysm (sIA) aneurysm causes intracranial hemorrhages that are associated with high mortality. Lipid accumulation and chronic inflammation occur in the sIA wall. A major mechanism for lipid clearance from arteries is adenosine triphosphate-binding cassette A1 (ABCA1)-mediated lipid efflux from foam cells to apolipoprotein A-I (apoA-I). We investigated the association of wall degeneration, inflammation, and lipid-related parameters in tissue samples of 16 unruptured and 20 ruptured sIAs using histology and immunohistochemistry. Intracellular lipid accumulation was associated with wall remodeling (p ¼ 0.005) and rupture (p ¼ 0.020).