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forces and changes in aneurysm morphology (luminal Hemodynamic and environmental factors both
factors), vessel wall integrity (extra-luminal factors), contribute to phenotypic modulation and eventually
immunological pathways, and patient-specific damage of and death to SMCs. [25] Initially, SMCs adapt
factors. [8,12-14] Clinical management and risk stratification to hemodynamic stress by migrating from the tunica
has generally relied on luminal characteristics (i.e. size, media into the intima to form myointimal hyperplasia.
location), and patient-specific risk factors, mainly However, in response to local signals, they also become
smoking, hypertension, heavy alcohol consumption, a secretory, pro-inflammatory cell type characterized by
positive family history, [15-18] but this does not differentiate upregulation of necrosis factor-κB signaling, increased
among aneurysms that have similar morphological production of MMP, IL-1β, tumor necrosis factor-α, and
features yet heterogeneous natural histories and initiation of pathways leading to SMC apoptosis. [34-40] As
pathological features. SMCs are largely responsible for the production of the
ECM, [41] their apoptosis results in decreased synthesis
Strong hemodynamic forces are thought to play a role of the new matrix, which exacerbates the effects of the
in initiating aneurysm formation as a result of high overabundant MMPs and further weakens the vessel
shear stress on vessel walls, which is greatest at the wall. MMPs are also produced by macrophages, [42,43]
bifurcations of cerebral arteries, where aneurysms which play a large role in neuroinflammation, and
occur most often. [19] Shear stress has been shown in intracranial aneurysms there is downregulation of
to lead to loss and damage of endothelial cells, loss tissue inhibitors of MMPs [42,44] and up-regulation of
of the internal elastic lamina (IEL), migration of proteolytic cathepsins. [45]
vascular smooth muscle cells (SMCs), and induction of
intracellular pathways in endothelial cells that induce In effect, the key processes believed to be responsible
pro-inflammatory cytokine release. [8,20-24] for weakening of the vessel wall, and potential
subsequent rupture, include enzymatic degradation
Endothelial injury is considered to be a necessary of the ECM, progressive loss of SMCs, and also the
first step in the aneurysm pathogenesis. [25,26] In decreased synthesis of new collagen fibers. [34] The
response to increased wall stress, endothelial cells result is a chronic state of remodeling and inflammation
undergo not only morphological, but also functional that ultimately results in critical weakening of the
changes, in which they upregulate production of vessel wall that is progressively less capable of
pro-inflammatory signals (cytokines, interleukins such withstanding hemodynamic stress, thus leading to
as interleukin-1β [IL-1β], leukocyte chemoattractants) growth and potentially rupture of the aneurysm. [25]
as well as matrix metalloproteinases (MMPs), [27] Inflammation causing enzymatic remodeling of the
resulting in recruitment of inflammatory cells and vascular ECM is a shared pathological mechanism
MMP-mediated enzymatic remodeling of the vessel also seen in several other vascular diseases including
wall. In addition, disruption of the IEL, which may atherosclerosis, abdominal aortic aneurysms, and
initially be in the form of shear stress-induced arteritides. [46-48] Atherosclerosis is itself a common
tears, is a characteristic histopathological feature feature in saccular intracranial aneurysms and as
of saccular aneurysms. [8,24] As the IEL is damaged, in abdominal aortic aneurysms, is associated with
the hemodynamic environment becomes turbulent aneurysmal progression and likelihood of rupture. [25]
within the lumen of the nascent aneurysm, leading The contribution of atherosclerosis and patient risk
to further endothelial damage and eventually factors, including hypertension and smoking are similar
de-endothelialization within the luminal surface of to its contribution to abdominal aortic aneurysms. [46]
the aneurysm. [22,28] This hemodynamic environment,
in concert with the exposed subendothelial matrix, Although the acute mechanism of aneurysm rupture
promotes formation of intraluminal thrombi which has yet to be fully elucidated, there are several key
consist of layers of platelets, red blood cells, factors that play a role. Clinically, a major predictor of
lipid-laden macrophages, and other leukocytes leading rupture is increased diameter > 7 mm, above which the
to increased oxidative stress, inflammation, and 5-year risk of rupture increases from 2.6% for 12 mm
further cell death. [14,29-30] The subsequent inflammatory to 40% for 25 mm. [49] In addition, using patient-specific
response within the damaged vessel wall consists computation flow dynamics analyses, it has been
of leukocytic infiltration with macrophages, T-cells, shown that small size of the impingement region
and mast cells, and is found in both ruptured and within the aneurysm, unsteady flow dynamics, and
unruptured aneurysms. [8,15,21,31-33] This inflammatory concentrated inflow jet are all associated with rupture
response results in progressive disorganization and of the aneurysm. [14,50,51] However, repeated studies have
loss of SMC and extracellular matrix (ECM) from shown that a higher degree of inflammatory infiltration
the media and open and stretched collagen in the is associated with aneurysm wall degradation and
adventitia. [8] subsequent higher risk of rupture. [13,31,52,53] Owing to

94 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015