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and vascular smooth muscle cell (VSMC) dysfunction ENDOTHELIAL CELL DYSFUNCTION, VASCULAR
are detailed and examined in relation to vascular REMODELING, AND INFLAMMATION
remodeling. The contribution of multiple cytokines
to a sustained pathologic inflammatory state and their Vascular remodeling is a complex process that is driven,
influence on aneurysm formation are outlined. Special in large part, by hemodynamic stresses along vessel
emphasis is placed on a key inflammatory mediator, walls. [18] The propensity for aneurysms to form at
tumor necrosis factor-α (TNF-α). The contribution of vessel branch points and the association of aneurysms
inflammatory cell infiltration, particularly the potential with environmental stimuli known to disrupt vascular
of macrophage-mediated rupture, is detailed. Finally, integrity (smoking, hypertension) highlights the role
future therapeutic implications of pharmacologic of abnormal blood flow and shear stress in aneurysm
modulation of the inflammatory response are discussed. formation. [17] High wall shear stress has been shown to
initiate activation of the inflammatory response. [20-22]
INTRACRANIAL ANEURYSMS AND THE Central to this process is the endothelial cells, which
INFLAMMATORY RESPONSE act as an interface between blood flow and the vessel
wall. [17] Through the process of mechanotransduction,
Multiple studies have identified various risk factors for these cells respond to the mechanical stimuli of
[5]
aneurysmal expansion and rupture. Genetics plays an shear, stretch, and flow by altering their physical
important role, with approximately 10% of SAH patients structure and initiating biologic signaling. [23-25] Multiple
having two or more family members also affected by mechanical sensors have been identified, including,
unruptured or ruptured aneurysms. [6,7] The propensity ion channels, integrins, cell adhesion molecules, and
for SAH within specific ethnic groups, particularly the G protein-coupled receptors at the apical and basal
Finish and Japanese populations, further highlights the surfaces of endothelial cells. [26-29] Activation of these
contribution of genetics. [8,9] Gender also appears to play sensors initiates intracellular cascades that result in a
a role, as women appear to more frequently develop sustained inflammatory response [Table 1].
intracranial aneurysms and perhaps suffer from ruptured
aneurysms more often than men. [10,11] Environmental Aoki et al. [30] demonstrated a direct link between shear
factors, particularly smoking, have been clearly linked stress and activation of the inflammatory cascade

to a higher incidence of SAH. [11] Additional studies in a rat model. Cyclooxygenase-2 (COX-2) activity,
have linked binge drinking to aneurysm rupture. [12,13] which is induced by hemodynamic force, generates
Chronically uncontrolled hypertension clearly correlates prostaglandin E2 (PGE2), leading to activation of the
[30]
with aneurysm formation in animal models and clinical pro-inflammatory mediator nuclear factor-κB (NF-κB).
studies have identified hypertension as a risk factor for Inflammation is then sustained through a positive
aneurysmal SAH. [10,11,14-16] feedback loop containing PGE2 and NF-κB, creating
an environment in which vessel wall degradation
Due to the variability in contributing risk factors, can occur. Inhibition of COX-2 or loss of the PGE2 Rp
attempts have been made to identify a unifying suppressed NF-κB-mediated chronic inflammation
underlying pathophysiologic mechanism that and was associated with a decreased incidence of
[5]
promotes aneurysm formation and rupture. There cerebral aneurysms. Additional support for the role of
is a tremendous mounting body of evidence that the NF-κB-mediated pathways in inflammation-induced
inflammatory response represents a common endpoint aneurysm formation is found in diminished aneurysm
that drives aneurysm evolution, which is succinctly formation and growth in rats treated with statins, which
summarized as initiation of development, growth, inhibit NF-κB activity. [31-33]
and potential rupture. [17] Hemodynamic stress and
disruption of blood flow, oxidative stress, injurious Evidence also exists that implicates angiogenesis
environmental elements (i.e. cigarette smoking and secondary to inflammation-driven endothelial cell
cocaine), and pro-inflammatory genetic alterations dysfunction as a significant contributor to aneurysm
all initiate a sustained and pathologic inflammatory formation. The presence of angiogenic growth factors,
response. [18,19] As a result, the intracranial vasculature including, vascular endothelial growth factor (VEGF)
is subjected to endothelial cell dysfunction, elevated and basic fibroblast growth factor, within aneurysm
[34]
inflammatory cell infiltration, detrimental changes walls has been well documented within the literature.
within the tunica media, and exposure to increased In pathologic states VEGF induces changes in the
concentrations of proteases. These processes lead to endothelium leading to increased permeability at
weakening, dilation, and remodeling of the vessel walls, intercellular junctions and activation of pathways
which are key components in aneurysm formation and resulting in the breakdown of the tunica media and
rupture. extracellular matrix. [35,36] Importantly, VEGF may also

Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015 69