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initiation and progression of IAs using animal models. SDF‑1 was present in the walls of both human and mouse
The authors were able to demonstrate that NF‑κB aneurysms. Hoh et al. [47] also found SDF‑1 promotes
participates in the initiation of IA formation through aneurysm wall angiogenesis through endothelial cell
transactivation of many downstream genes related to tube formation and macrophage infiltration. Inhibiting
macrophage recruitment and vascular inflammation, SDF‑1, using anti‑SDF‑1 blocking antibodies, supressed
such as MCP‑1, vascular cell adhesion molecule murine aneurysm wall angiogenesis and resulted in
1 (VCAM‑1), MMP‑2, MMP‑9, IL‑1β, and inducible the development of significantly fewer IAs compared
nitric oxide synthase (iNOS). [43] In addition, NF‑κB to control mice.
decoy oligodeoxynucleotides (ODNs), which inhibit
NF‑κB, abrogated the upreguation of inflammatory Macrophages mediate flow‑induced vascular
factors, including MCP‑1. In an additional study remodeling, in part, through the release of MMPs, a
conducted by the same group, Aoki et al. [44] linked process that under physiologic conditions, preserves
MCP‑1 expression in VSMCs with Ets‑1, a transcription vascular integrity and health. [39,49] However, increased
factor implicated in many vascular inflammatory levels of MMP expression, particularly MMP‑2 and
diseases. Ets‑1 binds to the promoter region of MCP‑1 MMP‑9, have been reported in IAs. [10,11,50,51] Studies using
resulting in increased Ets‑1 expression. Utilizing the broad‑based MMP inhibitors, such as doxycycline, have
knowledge obtained from previous studies on the role of shown significant reductions in the incidence of IAs
NF‑κB and Ets‑1, Aoki et al. [45] showed that treating rats in animal models. [49,52] Tolylsam, a selective inhibitor
with chimeric decoy ODNs, designed to simultaneously for MMP‑2, ‑9, and ‑12 also abolished the progression
inhibit NF‑κB and Ets‑1, reduced aneurysm size while of IA, although it did not reduce the incidence of total
thickening aneurysm walls of preexisting aneurysms. aneurysmal changes. [10] Using more refined inhibition
Furthermore, decreased expression of MCP‑1 and techniques, a greater understanding for the role of
reduced macrophage infiltration was observed in rats MMPs has materialized. Nuki et al. [52] showed that
treated with the decoy ODNs. MMP‑9 KO mice, but not MMP‑2 KO mice, diminished
the incidence of IAs. A separate study by Ota et al. [49]
Additional molecular signaling molecules associated also demonstrates a reduced incidence of IAs in MMP‑9
with macrophage‑induced aneurysm formation KO animals but not in MMP‑12 KO animals.
include tumor necrosis factor alpha (TNF‑α) and
stromal cell‑derived factor‑1 (SDF‑1). Several Whereas MMP‑9 is the main gelatinase, MMP‑12 is
studies have suggested that TNF‑α is a key mediator the main elastase secreted from macrophages. Since
in aneurysm development through the activation MMP‑12 appears to have no effect on aneurysm
of several cytokines and MMPs. [17‑19,46] TNF‑α has formation and rupture, other sources of elastases
been shown to upregulate MCP‑1, which in return are likely. Neutrophil elastase is involved in
attracts macrophages, thereby leading to additional atherosclerotic plaques and AAA and is produced
TNF‑α expression in a positive feedback loop. [18] by not only neutrophils but also macrophages and
Using TNF‑α KO mice, Starke et al. [18] demonstrated vascular endothelial cells. [53,54] Furthermore, neutrophil
a reduction in IA formation and rupture. Additional depletion studies inhibited AAA development through
studies using a synthesized TNF‑α inhibitor 3, a non‑MMP‑2 and non‑MMP‑9‑mediated mechanism,
6’dithiothalidomide (DTH) substantiated the results implying other mediators must exist, including the
from the KO experiments. Starke et al. [18] also showed possibility of neutrophil elastase. [55]
DTH to inhibit IA progression with fewer ruptured IA
in the treatment group compared to the control group. Another protease that is of interest is the cathepsin
Furthermore, using tumor necrosis factor receptor family (B, D, K, and S), which have been shown to be
superfamily member 1a (TNFR1) deficient mice, expressed in IAs and promote their progression. [56,57]
Aoki et al. [46] demonstrated suppressed IA formation Specifically, histological analysis of ruptured aneurysms
with decreased NF‑κB activation, reduced MCP‑1 exhibited a cluster of macrophages expressing cathepsin
and cyclooxygenase 2 (COX‑2) expression, and fewer D within the aneurysm wall where there was evidence
infiltrating macrophages. These results suggest that of collagen erosion. [31] Multiple studies suggest that
TNF‑α/TNFR1 signaling is critical in IA pathogenesis. a polarized macrophage population is associated
with a variety of diseases including atherosclerosis,
Stromal cell‑derived factor‑1 is an important chemokine inflammatory lung disease, and inflammatory
that promotes inflammation directly as well as through diseases of the nervous system. [58‑62] Two populations
angiogenesis. [47] Macrophage recruitment and retention of macrophages, the M1 (pro‑inflammatory) and
around new blood vessels has been shown to be mediated M2 (anti‑inflammatory) subtypes, have been identified.
by SDF‑1. [48] Expression of SDF‑1 in IAs was recently Predominance of the M1 subtype has been implicated
evaluated in a study conducted by Hoh et al., wherein in aneurysm progression and rupture.
[47]

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