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participation of mast cells in the pathogenesis and arterial walls. [68] There is a close relation between
rupture of IAs. [58] WSS, endothelial dysfunction, and the downstream
inflammatory reaction. [69,70]
Inflammatory cells interaction and arterial wall degeneration
Inflammation of arterial wall leading to formation Computational flow dynamic studies coupled with
of IAs is initiated by the infiltration of inflammatory histological studies of the aneurysm wall demonstrated
cells (macrophages, neutrophils and lymphocytes), which a correlation between hemodynamic conditions and
release proinflammatory cytokines and proteinases as inflammatory changes of intracranial arterial wall
well as chemokines and chemoattractant cytokines, leading to aneurysm formation and rupture. [10-13,70]
for the upregulating recruitment of inflammatory The most highlighted, even though, controversial
cells into the aneurysm wall. [60,61] In particular, levels factor studied is WSS, [12,71,72] which is the component
of MCP-1, chemokine (C-C motif) ligand-5 (CCL5), of the forces coplanar with the cross-section of the
monokine-induced-by-[gamma]-interferon, artery, originating from blood circulation and acting on
interferon-[gamma]-induced protein-10, Eotaxin, 2 arterial walls. [73] WSS is related to dynamic viscosity
other chemokines, IL-8 and IL-17 have been found to of blood, flow velocity parallel to the arterial wall and
be higher in blood samples taken from the lumen of distance of the vector to the wall. [73] Whether high or
human IAs than blood samples from femoral arteries low WSS is involved in the arterial wall inflammatory
of the same patients. [61] Inflammatory cytokines lead to damage, and development and rupture of IA are still
degradation and apoptosis of ECs and VSMCs through matter of debate. [74] Hemodynamics in IAs is complex
activation and upregulation of immune cells migration and includes areas of low and high WSS. [71,72] Several
[21]
and activity. Immune cells target not just cells but also studies show that exposure to abnormal WSS drives
ECM, the scaffolding structure that provides the arterial endothelium-mediated proinflammatory reactions, [75]
wall with tensile strength, elasticity, compressibility, MMPs activation, [76-79] apoptosis of ECs and VSMCs, [80]
adhesiveness as well as communicability between ECM degradation, and arterial wall remodeling. [36,81]
cells constituting the vessel wall. [17,18] In particular, Spatial gradients and changes in WSS magnitude
macrophages secrete MMPs resulting in excessive regulate ECs gene expression through the upregulation
proteolytic activity against connective tissue proteins, of transcription factors such as NF-κB under the
including collagens, elastin, and proteoglycans, which conditions responding to cytokines, free radicals
causes focal degradation of the vascular ECM and and other stimuli implicated in cell survival. [82-84]
may contribute to aneurysm formation and growth. [31] Oxidative stress in the arterial wall promotes IAs
Macrophages, in conjunction with lymphocytes, also formation inducing direct endothelial injury, VSMCs
act on VSMCs, for vessel wall remodeling. [21] Cytokines phenotypic modulation and apoptosis, recruitment and
and growth factors secreted by macrophages and invasion of inflammatory cells through upregulation
T-lymphocytes affect VSMCs phenotype changes and of chemotactic cytokines and adhesion molecules,
[62]
promote their apoptosis. [48,63,64] One of the key initiators and MMPs activation. [85] Oxidative stress reflects an
of apoptosis is interaction between the Fas receptor, imbalance between the production of ROS and the
which is expressed on the surface of both inflammatory arterial wall’s ability to readily detoxify the reactive
cells and VSMCs, and its ligand (Fas-ligand, Fasl), intermediates or to repair the resulting damages. The
which is expressed on the surface of macrophages and ability of the arterial wall to counteract oxidative
T-lymphocytes. [65] Their interaction induces VSMCs stress effects largely repose on NO action. [16] NO is an
apoptosis through upregulation of cytokines such as endothelium-derived relaxing factor that has several
TNF-α and interferons expressed by inflammatory actions translating in anti-atherosclerotic properties:
cells. [17,54,56,57] These cytokines promote also the synthesis it modulates vasomotor tone, inhibits expression of
of NO, another factor inducing apoptosis. [66] Apoptotic MCP-1 and VCAM-1, prevents propagation of lipid
loss of VSMCs induces arterial wall weakening by oxidation, inhibits VSCMc proliferation, decreases
reducing matrix synthesis. [63,64] platelet aggregation [86] and inhibits expression and
activity of MMPs. [86] Practically, all risk factors for
HEMODYNAMIC FACTORS INDUCE ARTERIAL arterial wall damage (hypercholesterolemia, diabetes,
WALL INJURY AND INITIATE WALL insulin resistance, arterial hypertension, cigarette
INFLAMMATION smoking) reduce production of endothelial NO
through increased production of superoxide and
Endothelial dysfunction initially and vascular other ROS. [16,86-90] These strong oxidants both disrupt
remodeling subsequently are triggered by shear NO-mediated arterial wall protection decreasing
stress. [67] This explains why IA is commonly found at availability of NO and promote arterial wall
−
arterial junctions, bifurcations or abrupt vascular angles inflammation increasing ONOO production. [16,86-90]
where excessive hemodynamic stresses are exerted on Under physiological conditions, unidirectional laminar

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