Page 71 - Read Online

shear stress increases NO availability through a biphasic by the WSS in modulating cytokine-induced adhesion
action: within seconds after stress the endothelial nitric molecule expression in ECs. Although the processes by
oxide synthase (eNOS) enzyme expressed in ECs is which hemodynamic factors affect inflammation of the
activated by a calcium-independent mechanisms. [91] artery wall is incompletely known, vascular remodeling
Subsequently, eNOS expression is upregulated through in response to abnormal WSS correlates with increased
NF-κB activation by a transient, one hour lasting, ECs and VSMCs apoptosis, [98,99] with upregulation
increase in eNOS mRNA transcription and a sustained of MMPs activity in both ECs [33] and VSMCs [36] and
increase in eNOS mRNA stability. [92] However, NF-κB with upregulation of several transcription factors and
activation leads also to an increased expression of inflammatory cytokines by inflammatory cells. Along
[18]
pro-inflammatory genes encoding cytokines, VCAM-1, these lines, Wang et al. [82] showed in canine models
ICAM-1, tissue factor and MCP-1. [16,86-90] At a first that in areas of high shear stress (arterial bifurcations),
glance, the NF-κB mediated protective and damaging aneurysm wall remodeling is associated with IL-1β and
effect appears to be contradictory. Nonetheless, the MMPs expression along with a loss of eNOS expression.
evidence of a negative feedback pathway on NF-κB In line with these findings, EC injury was found by
activation mediated by NO production resolves Jamous et al. [100,101] to be the earliest change in aneurysm
this apparent paradox. If eNOS levels are relatively wall, followed by the formation of an inflammatory
high, sufficient NO is produced to shut down NF-κB zone that leads to proteolytic destruction of the vascular
activation soon after shear is applied to endothelium ECM by MMPs and ultimately to aneurysm formation.
through a classical negative feedback pathway. [16]
Conversely, if eNOS levels are relatively low, NF-κB In summary, under physiologic condition shear stress
activation persists enough to restore eNOS to normal promotes both endothelial NF-κB upregulation and
levels in order to ensure a long-lasting protection immediate eNOS activation. In turn, NF-κB triggers
to ECs. The double effect of NF-κB activation also both transient upregulation of eNOS and increased
explains why shear stress may reveal both harmful eNOS stability. This results in increased NO synthesis.
and protective to endothelium. As a matter of fact, NO protects arterial wall through a “direct” action on
in case of alteration of the inhibitory limb of the it as well as “indirectly” through a negative feedback
NO-mediated negative feedback, the proinflammatory on NF-κB activation. When the chain of events in red
action of shear stress prevails, leading to endothelium prevails, shear stress sustains arterial wall protection.
damage, with elongation, migration, change in density, Failure of NO-mediated direct and/or indirect arterial
and loss of ECs and to VSMCs phenotype change with wall protection shifts the balance towards inflammation.
acquisition of pro-inflammatory/pro-matrix remodeling
properties. [17,50,61] ROS may also play a role in the When the degeneration in the arterial wall, including loss
pathogenesis of IAs. [93,94] Aoki et al. [95] demonstrated of endothelial and smooth muscle cells and degradation
the upregulation of genes producing ROS and the of ECM are not healed, chronic remodeling of tissue
downregulation of ROS-eliminating genes in a murine takes place to alter the biomechanical properties of
model of IAs. Moreover, the same study showed a arterial wall and aneurysm formation, which eventually
similar effect of edaravone, a free radical scavenger, rupture [Figure 1]. [63,64]
and of the deletion of ROS-producing gene: in two
separate groups of animals both effectively inhibited IAs INFLAMMATORY BIOMARKERS AND
formation by suppressing inflammation in aneurysmal ESTIMATION OF RISK OF RUPTURE
walls. [95] Moreover, low WSS may provide upregulation
of proinflammatory cytokines and their receptors, such Giving that considerable evidence suggest the
as IL-1α, IL-1 receptor, IL-6, and MCP-1. [96] In addition, involvement of inflammation in development and
an in vitro study showed that WSS on ECs causes a rupture of IAs, [19-25,31,35-41,48-64,70,76-81,93,94,99-101] preoperative
differential modulation of TNF-α-induced expression noninvasive assessment of inflammatory status of the
of adhesion molecules such as ICAM-1, VCAM-1, aneurysm wall may guide management of unruptured
and E-selectin by reducing intracellular ECs ROS IAs. [102-105] One possible tool to identify rupture-prone
levels. [97] This may cause inhibition of TNF-α-induced IAs is ferumoxytol-enhanced magnetic resonance
VCAM-1 and E-selectin expression in ECs through imaging (MRI). [102-104] Ferumoxytol is an ultrasmall
inhibition of NF-κB activation. [97] However, the same superparamagnetic particle of iron oxide that reveals
authors showed that WSS-induced production of phagocytic activity of inflammatory cells because
TNF-α stimulates the expression of another adhesion it is cleared by macrophages. [102-104] Ferumoxytol is
molecule, ICAM-1. [97] These apparently discordant hypointense on MRI T2*-weighted gradient echo
findings indicate that a more thorough study of the sequences and hyperintense on T1-weighted spin echo
cross-talk between these signaling molecules may shed sequences. It is detected inside blood vessels for ≤ 72 h
further light onto the biological end-points produced and begins to clear within 24 h from injection. Its early

Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015 63