- In normal arteries, myointimal hyperplasia is an adaptive mechanism in response to hemodynamic stress or mechanical injury. Pads of myointimal hyperplasia are formed when endothelial damage from injury or stress induces a change in the phenotype of medial smooth muscle cells that promotes their migration to and proliferation at the damaged endothelial lining. The histopathologic resemblance of unruptured intracranial aneurysm walls to myointimal hyperplasia suggests that the aneurysm wall reacts similarly to hemodynamic stress by increasing cell proliferation and matrix synthesis. However, it is still unclear whether the myointimal hyperplasia in aneurysms is an adaptive mechanism of the vascular wall to compensate for excessive stress or whether it contributes to weakening of the wall. Unlike terminally differentiated skeletal and cardiac muscle cells, arterial smooth muscle cells can change in phenotype. In cerebral aneurysms, the smooth muscle cells go from a “contraction”-oriented phenotype to a “proinflammatory and matrix remodeling” phenotype, which suggests that alterations in smooth muscle cells play a role in pathogenesis.
- Results of histologic studies suggest that intracranial aneurysm walls rupture as a consequence of matrix degeneration and decellularization, which may be the result of direct vascular stress or injury or may correspond to defects in homeostatic maintenance or repair mechanisms. Although it is still unclear how risk factors for subarachnoid hemorrhage—such as smoking, hypertension, female gender, previous subarachnoid hemorrhage, and age—contribute to rupture, data suggest that proteolysis, programmed cell death, inflammation, and hemodynamic stress are associated with aneurysm wall degeneration and rupture.
- Extracellular matrix components are constantly being synthesized and degraded. In comparison with normal intracranial arteries, aneurysm tissue, especially ruptured aneurysm tissue, displays increased activity or expression (or both) of matrix-degrading proteases that regulate remodeling of the arterial wall. Prominent in aneurysm walls are matrix metalloproteinase (MMP)–2 and MMP-9, which are classified as gelatinases and are capable of degrading both elastin and denatured collagen. In a series of 23 patients with intracranial aneurysms, Bruno and associates found focal areas of gelatinase activity attributable to MMP-2 and MMP-9 in both ruptured and unruptured aneurysms. Increased protease activity correlated with increased expression of MMP-2, plasmin, and membrane-type MMP, the latter two being involved in activation of MMP-2. Increased serum levels of elastase have also been observed in patients with aneurysms. Furthermore, cathepsin D–expressing cells have been found in aneurysm walls in regions where the collagen layer was degraded. Cathepsin D is an endopeptidase that can also digest extracellular matrix proteins.
- Data suggest that increased proteolysis may also contribute to rupture of intracranial aneurysms. In a series of 30 patients with aneurysms, Jin and colleagues found that messenger RNA (mRNA) levels of MMP-2 and MMP-9 were higher in ruptured aneurysms than in unruptured aneurysms. Levels of MMP-2 and MMP-9 were elevated in relation to their inhibitors (called tissue inhibitors of MMPs [TIMPs]) in ruptured aneurysms. Patients with ruptured aneurysms had higher serum MMP-2 and MMP-9 levels than did those with unruptured aneurysms. Upregulation of elastase activity has also been observed in the arterial walls of ruptured aneurysms, in comparison with unruptured aneurysms.
- Very few cells undergo programmed cell death (apoptosis) in normal arterial wall tissue. In contrast, many apoptotic cells are found in intracranial aneurysm walls, especially in ruptured aneurysms. Experimental and clinical studies have shown that the decreased number of smooth muscle cells in aneurysm walls is caused primarily by apoptosis. Higher apoptosis levels were also found in the meningeal and superficial temporal arteries in patients with ruptured aneurysms than in patients with unruptured lesions. In a series of five ruptured aneurysms, Hara and coworkers found that many apoptotic cells were localized in the neck and dome of aneurysms, close to the rupture point, whereas no apoptosis was detected in control arteries. These results suggest that apoptosis plays an important role in the development and rupture of intracranial aneurysms.
- The events that trigger apoptosis in aneurysm walls are unclear. It had been proposed that apoptosis is induced by cytokines released by inflammatory cells that infiltrate aneurysm tissues. Jayaraman and associates showed that mRNA and protein expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and its proapoptotic downstream target, Fas-associated death domain protein, are increased in ruptured aneurysms, which suggests that TNF-α has a role in promoting inflammation and subsequent apoptosis in aneurysm walls.
- A role for the c-Jun amino-terminal kinase (JNK) pathway in apoptosis in intracranial aneurysms has also been proposed. Inflammatory signals are capable of stimulating JNK (a member of the mitogen-activated protein kinase family) to initiate apoptosis through phosphorylation of the c-Jun transcription factor. In a series of 12 intracranial aneurysms and 5 control vessels, Takagi and coworkers found that phosphorylation of JNK and its target, c-Jun, was increased in aneurysm tissues in regions where apoptosis in smooth muscle cells was also increased. In a series of 12 ruptured and 12 unruptured aneurysms, Laaksamo and associates found that JNK phosphorylation in the RNA-binding protein p54 was 1.5-fold higher in ruptured aneurysms than in unruptured aneurysms. Furthermore, phosphorylation of p54 JNK and the protein levels of both JNK and c-Jun were found to be correlated with aneurysm size.
- The presence of macrophages, T cells, B cells, immunoglobulin antibodies, and activated complement in intracranial aneurysm walls, especially in ruptured aneurysms, indicates that active innate and adaptive immunologic reactions are associated with aneurysm formation and rupture. Upregulated expression of the proinflammatory chemokine monocyte chemoattractant protein-1 in the aneurysm wall has also been observed. Even though mRNA of monocyte chemoattractant protein-1 was not detectable in normal arteries, it was often observed in the intima of aneurysmal walls and appeared to be expressed in the cytoplasm of fibroblast cells that assembled with monocyte-like cells. The extent of inflammatory cell infiltration and complement activation appeared to be higher in ruptured aneurysms than in unruptured aneurysms.
- Further evidence of the development of active immune reactions in intracranial aneurysm specimens was demonstrated in a microarray study by Krischek and colleagues, who compared the global transcription profiles of six ruptured and four unruptured aneurysm tissues with the profiles of four control arteries. Genes involved in antigen presentation, such as major histocompatibility complex class II genes, emerged as those with the highest upregulation in the aneurysm samples.