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Pathogenesis of Abdominal Aortic Aneurysms
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Figure 2. (A-I) Histological images of aortic aneurysms at 3, 7 and 15 dps in rats from group A, stained
with HE, PS or RES. Note the extensive remodeling of the aortic wall, the abundant collagen deposits
and the destroyed elastin fibers, as well as the presence of inflammatory cells. (J-L) sections of aortas
from the control animals for comparison. Bar = 50 µm.
Large numbers of inflammatory cells were observed in the aneurysmatic walls in the rats
in group A. The number of neutrophils was significantly increased from 3 dps and remained
high until 15 dps (P<0.001; figure 4), whereas no change was observed in the rats in group C.
Similarly, the macrophages were high 3 dps in group A (P<0.001; figure 4). Both types of
inflammatory cells (neutrophils and macrophages) were the predominant cells in the
aneurysm wall. The number of B and T lymphocytes was also elevated in the rats in group A
throughout the experiment (P<0.001), although the values were less than those of neutrophils
and macrophages. The number of SMC/myofibroblasts and the amount of neovascularization
was increased in the rats in group A throughout the experimental period (P<0.001; figure 4).
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Figure 3. Bar graphs demonstrating various morphometric parameters analyzed in both groups. The
data shown are the means ± SD (n = 6 per group); *P < 0.05, **P < 0.01 and ***P < 0.001.
Figure 4. Bar graphs demonstrating the inflammatory response, number of SMCs and
neovascularization in both groups. The data shown are the means ± SD (n = 6 per group); *P < 0.05,
**P < 0.01 and ***P < 0.001.
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Pathogenesis of Abdominal Aortic Aneurysms
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Figure 5. Bar graphs demonstrating the iNOS and nitrotyrosine levels in both groups. The data shown
are the means ± SD (n = 6 per group); *P < 0.05, **P < 0.01 and ***P < 0.001.
These alterations are directly related to the striking increase in the levels of inducible
nitric oxide synthase (iNOS) and nitrotyrosine in the aneurysms from 3 dps until the end of
the experiment (group A; P<0.05; figure 5). However, there were no changes in presence of
inflammatory cells or SMC/myofibroblasts, in vascularization or in the levels of iNOS and
nitrotyrosine were observed in the rats in group C.
Figure 6. Bar graphs demonstrating the activity of MMP-2 and MMP-9 and the expression level of
TIMP-1 and 2, obtained by densitometric analysis of western blots. The data shown are the means ± SD
(n = 6 per group); *P < 0.05, **P < 0.01 and ***P < 0.001.
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Densitometric analysis revealed that the expression of both forms of MMP-2 (pro and
active) and of MMP-9 were significantly higher in the aneurysms (group A; P<0.05; figure 6)
after 3
rd
dps. Similarly, the expression of TIMP-1 was increased in aneurysms (P<0.05; figure
6) within 3 dps and expression of TIMP-2 was increased within 7 dps, as demonstrated from
analysis of western blots (P<0.001; figure 6). The expression of MMP-2, MMP-9, TIMP-1
and TIMP-2 was not altered in the rats in group C.
5.1.3. Discussion
In previous work performed in our laboratory, we created a new model of AAA induction
by combining two potential causes of metalloproteinase (MMP) secretion: acute inflammation
and turbulent blood flow [32]. In isolation, these causes were insufficient to provoke arterial
dilatation and aneurysms but when combined, the abundant MMP-2 and MMP-9 secretion
and activation promoted elastin degradation, wall remodeling and aneurysm formation. The
technique of the new model was efficient, causing the development of extraordinarily dilated
aneurysms with a morphology similar to that of human abdominal aneurysms in only 3 days.
The pathology of AAA is complex and poorly understood. Destruction of extracellular
matrix components and marked local inflammatory cell infiltration are the striking histologic
features of human AAA tissue [99]. The persistent inflammatory state in AAA is held
responsible for the proteolytic imbalance that underlies the extensive matrix degradation by
proteases [3, 38]. A strong relationship between vascular inflammation and the progression of
abdominal aortic aneurysms has been demonstrated by clinical findings and experiments on
animal models. Aneurysms are characterized principally by a chronic inflammatory response
accompanied by a proteolytic imbalance. Increased proteolytic activity in the disease is
responsible for the increased matrix turnover and the progressive weakening of the aortic wall
[3]. Inflammatory responses contribute to the acceleration MMP secretion in aortic
aneurysms. Studies on mRNA and protein have demonstrated increased local expression of
the MMPs as well as an imbalance between the expression of MMP and the expression of
their naturally occurring inhibitors, the tissue inhibitors of MMPs (TIMPs). MMP activity can
be restrained by the natural inhibitors (TIMPs). Thus, it is more likely that a particular
expression pattern of MMPs/TIMPs rather than up- or down-regulation for the degradation of
the aortic ECM. Generally, when the expression of MMPs is increased, the expression of
TIMPs is decreased [100]. Revealing this distinct expression pattern in aortic tissue requires
screening large number of MMPs and/or TIMPs.
The specifically high expression of MMP-2 and MMP-9 that is observed in aneurysmal
tissue plays a pivotal role in the formation of aneurysms [32]. MMP-9 is one of the most
abundant elastolytic proteinases secreted by human AAA tissues. It is produced primarily by
the aneurysm-infiltrating macrophages at the sites of tissue damage and its expression appears
to correlate with an increasing aneurysm diameter [30]. MMP-2 expression is elevated in
human AAAs and is primarily the product of the resident mesenchymal cells [101]. Our
findings are in agreement showed a remodeling wall characterized by the total destruction of
elastin fibers and the progressive deposition of collagen in the aortic wall, associated with
inflammatory responses, mainly of the macrophages and neutrophils. High levels of
expression of MMP-2 and -9 were observed in the aneurysmal tissue, similar to what has been
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Pathogenesis of Abdominal Aortic Aneurysms
71
reported shown in the literature. The expression of TIMP-1 and -2 was also high in
aneurysmal tissue, most likely as an effort to counteract the activity of the MMPs.
The blood flow conditions clearly influence intramural vascular inflammation, although
the mechanisms underlying these influences are not completely understood [25, 102]. The
narrowing of the artery seriously perturbs the overall laminar nature of the blood flow and
generates complex zones of accelerating, decelerating and turbulent flow [103-105],
promoting proinflammatory gene expression [104]. The shear conditions also regulate the
expression of cytokines, chemokines and growth factors [106]. Optimization of a pig AAA
model was recently described; this model combined the effect of elastase on the aortic wall
with turbulent blood flow caused by a stenosing cuff, reinforcing the concept that turbulent
flow in the aorta lumen has a significant effect on the progression of AAA [96].
Hemodynamic conditions also regulate oxidative stress-related gene products relevant to
AAA disease. Increased blood flow and antegrade shear stress stimulate antioxidant, anti-
inflammatory, and anti-apoptotic gene expression in vascular cells, whereas non-laminar or
reduced antegrade stress augments oxidative stress, inflammation and cell loss [107]. One of
the potential mechanisms of NO-mediated tissue damage is its capacity to amplify the effects
of the proinflammatory cytokines on various cell types, leading in part to increased
expression of MMPs [108]. Reactive nitrogen intermediates may also accelerate connective
tissue destruction by promoting the activation of MMPs [109]. In addition, protein nitration
causes direct oxidative damage to connective tissue structural proteins, such as elastin [110].
The potential role for oxidative stress in catalyzing aortic aneurysmal degeneration was
recently emphasized by Miller and associates [111], who found evidence of increased ROS-
generating enzyme activity, increased superoxide production and molecular and morphologic
evidence of oxidative tissue injury in human AAA tissue. To investigate the possibility that a
high local production of NO contributes to aneurysmal degeneration, we examined protein
tyrosine nitration and the expression of some isoforms of nitric oxide synthase (NOS) during
aneurysm formation in the AAA rat model. Our study demonstrated that aneurysmal
degeneration was associated with extensive production of nitrotyrosine and markedly
increased expression of inducible NOS (iNOS) in the aortic wall within 3 dps, which
coincided with an increase in the levels of MMPs. Interestingly, Dalman et al. (2003) reported
that ROS, which are extracellular pro-aneurysmal factors, also act intracellularly to promote
the chemotaxis, activation and proinflammatory cytokine release of monocytes [107].
In summary, the results of this study are valuable for our understanding of the link
between vascular wall inflammation and aneurysm disease, demonstrating that inflammatory
cells, MMPs, and iNOS play a requisite role in the process of induced experimental
aneurysmal degeneration in the rat. The validation of experimental models of AAA will
provide insight into the mechanisms of the progression of this disease in humans. A recent
interest in developing new therapeutic strategies for patients with small asymptomatic AAAs
has led to greater efforts to define the molecular mechanisms that underlie aneurysmal
degeneration. Thus, we believe that our model has great potential for improving
understanding of the etiopathogenesis of AAAs, as well as for investigating new therapeutic
treatments.
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6. FUTURE DIRECTIONS
Clearly, current requirements of basic research into AAA have encompassed a broad
spectrum of potential areas for research. Conceptual models of aortic aneurysm disease have
traditionally focused on the mechanical aspects. Consequently, surgical solutions have
dominated the therapeutic approach to this disorder. Nevertheless, with the growing
recognition of the prevalence of small AAAs and the unfavorable natural history of these
lesions, it is evident that a wide range of multidisciplinary research is needed. It is hoped that
rapid progress in AAA research will attract investigators with expertise in various relevant
fields of study to apply and integrate approaches involving vascular physiology, tissue-
specific pathology, vascular cell biology, molecular analysis of gene expression, clinical
research and molecular genetics. Careful characterization and the creative use of human tissue
resources will accelerate this endeavor, as will the development of more animal models of
AAA. Furthermore, those who want to explore new paths for the clinical management of
small AAAs and can generate testable hypotheses are needed to analyze the factors
influencing the progression of aneurysmal disease under different clinical conditions. These
efforts must necessarily include doctors specializing in vascular surgery, cardiology and
vascular medicine as well as basic researchers focused on various aspects of tissue biology,
inflammation and immunology, genetics and molecular biomechanics. Strong collaborations
between basic and clinical researchers are thus necessary for greater understanding of the
etiology, pathophysiology and natural history of aortic aneurysms [112].
ACKNOWLEDGMENTS
This work was supported by grants from the Fundação de Apoio ao Ensino, Pesquisa e
Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da
Universidade de São Paulo (FAEPA) and Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP; 2012/00601-1). SGR is a research scientist at CNPq.
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