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Vascular smooth muscles cells (VSMCs), mainly found MEDIATORS OF INFLAMMATION
in the media layer, are recognized as major producers
of matrix in the vessel wall. Upon endothelial injury, Human and animal studies have both shown that
intimal thickening occurs as VSMCs migrate into the inflammatory cells and mediators are involved in IA
intima and proliferate. [7,10] Phenotypic transformation pathogenesis [Figure 1]. A number of these inflammatory
is seen in these migrated VSMCs as environmental cells and mediators are highlighted in this section, with
change induces a switch from a contractile phenotype a special focus on the most recent investigation. Mast
to a synthetic pro-inflammatory matrix remodeling cells infiltration into the aneurysm vessel wall has
phenotype in these cells. [11] Nakajima et al. [12] showed been illustrated throughout the pathophysiological
phenotypically modulated VSMCs have lower chronology of IA development. [17] Ishibashi et al. [17]
expression of contractile smooth muscle myosin analyzed mast cells levels at different time intervals
heavy chain isoforms when immunohistochemically following aneurysm induction in a rat model and
stained. Furthermore, the group observed decreases in discovered that the number of mast cells in the IA walls
contractile protein staining intensity in ruptured IA, significantly increases over time. To further understand
suggesting VSMC phenotypic modulation is related to mast cells’ role in the aneurysm pathogenesis, mast cell
a rupture mechanism. degranulation inhibitors, tranilast and emedastine, were
administered into an aneurysm-induced rat model. The
Endothelial cells are also affected by the hemodynamic inhibitors had an impact on aneurysm progression by
insult. As blood flows, mechanical stimulus has notable decreasing aneurysm size, as well as the extent of media
affects on the cells of the vascular system. Shear stress thinning in the induced IAs. Mast cells’ contribution to
[13]
influences arterial physiology, in particular, the cellular the inflammatory process was simultaneously studied
function of the vessel wall. Consequently, IAs develop in through the analysis of mast cell degranulation’s
[13]
vessel regions exposed to high hemodynamic stress such effect on cultured arterial smooth muscle cells of rat
as arterial bifurcations and sharp angles. Endothelial IAs. The group found that mast cell degranulation
[7]
cells under laminar flow become aligned with the flow promoted MMP-2, MMP-9, and iNOS expression. [17]
but endothelial cells under turbulent flow become Based on previous findings that iNOS deficiency leads
cuboidal due to F-actin reorganization. Experimentally, to a decrease in apoptotic smooth muscle cell death,
[14]
endothelial cells respond to hemodynamic stress with the Ishibashi et al. [17] and Sadamasa et al. [18] suggested that
up-regulation of the inflammatory mediator, prostaglandin the inhibition of mast cell degranulation impacts the
E receptor 2 (EP2), during the formation of cerebral process of media thinning through its induction of
aneurysms. When shear stress was applied to primary iNOS. The authors also concluded that the decrease
[15]
endothelial cells, EP2 was found to be up-regulated. in media thinning results from mast cells’ modulation
[15]
The stimulation of EP2 in primary endothelial cells also of MPP-2 and MMP-9 expression. [17,19] Overall, these
led to the activation of the transcription factor NF-κB, a data suggest that the degranulation of mast cells plays
well-studied transcriptional mediator of inflammation a role in IA formation.
in IA. [15]
T cells and macrophage infiltration have found to be
As cerebral vessel walls undergo change during associated with human cerebral aneurysm rupture. [20]
aneurysm development, the formation of new Kanematsu et al. studied leukocyte infiltration into
[21]
vessels, angiogenesis, also contributes to aneurysmal the aneurysm wall of an aneurysm-induced mouse
progression. [16] Angiogenesis indirectly advances model and found macrophages to be one of the dominant
the inflammatory process of aneurysm progression leukocytes present. Cerebral aneurysm incidence was
by aiding in the delivery of inflammatory cells to found to be significantly attenuated in mice with lower
vessel walls. Hoh et al. [16] recently showed that macrophage levels as well as in mice with inhibited
stromal cell-derived factor-1 (SDF-1) is expressed monocyte chemotactic protein-1 (MCP-1), a macrophage
in murine carotid IAs, murine circle of Willis IAs, chemoattractant, when compared with wildtype mice.
[21]
and human cerebral aneurysms. The study found Certain proteinases secreted by macrophages have been
increased levels of progenitor cells expressing the found to be involved in the vascular remodeling of
SDF-1 receptor, CXCR4, in mice with carotid and aneurysm formation. Aoki et al. demonstrated that in
[19]
cerebral aneurysms. Study findings also showed SDF-1 aneurysm-induced rats, the expression of MMP-2 and
to promote endothelial cell migration, endothelial MMP-9, was present in the arterial wall undergoing the
cell tube formation (angiogenesis), and macrophage beginning stages of aneurysm formation. This expression
migration. [16] Inhibition of SDF-1 in the murine model was found to increase alongside the progression of
significantly decreased the amount of endothelial cells the studied cerebral aneurysms. Macrophages were
and capillaries in the aneurysm wall, and the overall determined to be the main secretes of the MMPs in the
rate of aneurysm formation was reduced. [16] study. Further connection has been found between
[19]

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