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studies have shown Ets-1 to play a role in the rupture of intracranial aneurysms. Multiple studies
regulation of vascular inflammation, pathologic have demonstrated increased levels of TNF-α within
remodeling, and angiogenesis. [66-69] Aoki et al. [65] the cerebral circulation in response to injury or
demonstrated upregulation and activation of Ets-1 in ischemia. [87,88] Elevated levels of TNF-α mRNA have
intracerebral aneurysm VSMCs, strongly implicating been demonstrated in intracranial aneurysms with
this inflammatory transcription factor in aneurysm reverse transcription-polymerase chain reaction. [89]
evolution. Plasma TNF-α is also increased in aneurysm patients
while additional authors have reported an association
Vascular smooth muscle cells in a secretory state generate between single-nucleotide polymorphisms in the TNF-α
increased monocyte chemoattractant protein-1 (MCP-1), gene and an increased risk of aneurysm incidence and
a chemokine involved in the attraction and migration of rupture. [90-94]
monocytes and macrophages to areas of damaged tunica
media. [70] MCP-1 upregulation has been demonstrated Tumor necrosis factor-α is a well-established mediator of
in the early stages of cerebral aneurysm formation in inflammation and apoptosis, working through multiple
rat models, and MCP-1 blockade resulted in decreased receptors to modulate various cellular responses to
macrophage infiltration and aneurysm progression. [71,72] injury. Tumor necrosis factor-α receptor 1 (TNFR1)
Chalouhi et al. [73] reported high levels of MCP-1 in the primarily binds the soluble form of TNF-α and plays a
lumen of unruptured cerebral aneuryms, implicating central role in TNF-α-induced cellular signaling. [95,96]
this chemokine in early aneurysm formation. Importantly, TNFR1 contains a death domain that plays
a role in TNF-α-mediated apoptosis. [97,98] A second
Normal maintenance of the extracellular matrix receptor, TNFR2, is activated by membrane-bound
is dependent on the balance between MMPs TNF-α and primarily found on endothelial and
and their inhibitors, tissue inhibitors of matrix immunomodulatory cells. Activation of TNFR1 signals
metalloproteinases (TIMPs). [52] Imbalance in this apoptosis through the activation of the Fas-associated
system results in excessive breakdown of the collagen death domain (FADD), which in turn, binds and
and elastin of the extracellular matrix and resultant activates pro-caspase 8. Ultimately, this pathway leads
vessel wall weakening, a key contributor to aneurysm to the activation of multiple proteases that result in
[2]
development and rupture. MMPs and TIMPs have been apoptosis. Jayaraman et al. postulate that a complex
linked to the development of atherosclerotic lesions interaction between TNF-α and both receptors induces
and the genesis of abdominal aortic aneurysms. [12,74-80] and promotes aneurysm growth.Initially, endothelial
Immunohistochemistry and western blotting have activation is driven by TNFR2 and membrane-bound
demonstrated the presence of MMPs within the walls of TNF-α. Activated endothelial cells generate high
intracranial aneurysms. [81,82] In SAH patients, elevated concentrations of soluble TNF-α, which interacts with
serum MMP-9 levels have been documented, with the TNFR1, leading to endothelial cell dysfunction
normalization occurring by postbleed day 12. Cigarette and death. Endothelial cell death, in turn, creates
[83]
smoke, a well-established, inflammatory stimulus for increased vascular permeability, thereby creating
aneurysm initiation and growth, has been demonstrated multiple pathways for macrophage infiltration, MMP
to induce macrophage differentiation and increased generation, and loss of the VSMC layer. An additional
release of MMP-2/9. [84] In a comparison of smokers and receptor, tTNF-Rp55, initiates apoptosis through the
nonsmokers, the carotids of smokers demonstrated induction of caspases. [89] The TNF-Rp55 also induces
elevated levels of MMPs and a decreased concentration the recruitment and activation of caspases through
of TIMPs and elastin compared to nonsmokers. [85] interaction with the FADD protein. [99] Documented
increased expression of the FADD protein in human
Laboratory investigations also support derangement aneurysms also supports TNF-α-mediated apoptosis
of MMP and TIMP interactions as a key component as a causative factor in aneurysm formation. [89]
in the aneurysm pathogenesis. In a rat model, Aoki
et al. [51] demonstrated increased levels of MMP-2 and Tumor necrosis factor-α also appears to play an
MMP-9 in aneurysm walls, with increasing expression important role in the pathologic VSMC changes
as aneurysms progressed. Ali et al. [86] reported MMP observed in aneurysm formation and rupture, driving
stimulation by cigarette smoke extract in rat cerebral these cells to change from a contractile to a synthetic
VSMCs in vitro and in carotid VSCMs in vivo. and pro-inflammatory phenotype. Furthermore, the
secretory phenotype of VSMCs participates in the
TUMOR NECROSIS FACTOR‑α secretion of TNF-α when exposed to inflammatory
stimuli. [100,101] Ali et al. [102] demonstrated TNF-α to
Tumor necrosis factor-α has emerged as a potential key suppress expression of contractile genes and induce
contributor in the generation, growth, and eventual the expression of pro-inflammatory genes in VSMCs

Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015 71