BASIC SCIENCE REVIEW
Current concepts in the pathogenesis of
abdominal aortic aneurysm
Gorav Ailawadi, MD, Jonathan L. Eliason, MD, and Gilbert R. Upchurch Jr, MD, Ann Arbor, Mich
Abdominal aortic aneurysms (AAAs) are a significant
medical problem with a high mortality. The primary diag-
nostic code for AAA accounts for approximately 150,000
inpatient hospital admissions per year. The most recent
published data from the National Vital Statistics Report on
Deaths from the year 2000 show that AAAs and aortic
dissection composed the tenth leading cause of death in
white men 65 to 74 years old and accounted for nearly
16,000 deaths overall. The year 2000 National Hospital
Discharge Summary reports more than 30,000 open oper-
ations for repair of AAAs in the United States. Understand-
ing the cause of AAAs therefore becomes an important
undertaking.
The pathogenesis of AAAs is complex and multifacto-
rial. Histologically, AAAs are characterized by destruction
of elastin and collagen in the media and adventitia, smooth
muscle cell loss with thinning of the medial wall, infiltration
of lymphocytes and macrophages, and neovascularization.7
Inflammation is a common underlying feature of both
aneurysm disease and atherosclerosis. However, atheroscle-
rosis is primarily found within the intima and media,
whereas aneurysm disease typically affects the media and
adventitia. A National Heart, Lung and Blood Institute
Request for Applications (HL-99-007) entitled “Patho-
genesis of Abdominal Aortic Aneurysms” identified four
mechanisms relevant to AAA formation: proteolytic degra-
dation of aortic wall connective tissue, inflammation and
immune responses, biomechanical wall stress, and molecu-
lar genetics.19
From the Jobst Vascular Research Laboratories, Section of Vascular Surgery,
Department of Surgery, University of Michigan Medical School.
Supported by an American College of Surgeons Resident Research Scholar-
ship (G.A.) and a National Institutes of Health Mentored Clinical Scien-
tists Development Award (K08 HL67885-01) Lifeline Foundation Re-
search Award (G.R.U.).
Competition of interest: none.
Reprint requests: Gilbert R. Upchurch, Jr, MD, University of Michigan
Medical Center, 2210 Taubman Health Care Center, 1500 E Medical
Center Dr, Ann Arbor, MI 48109-0329 (e-mail: riversu@umich.edu).
J Vasc Surg 2003;38:584-8.
Copyright © 2003 by The Society for Vascular Surgery.
0741-5214/2003/$30.00 ⫹ 0
doi:10.1016/S0741-5214(03)00324-0
584
PROTEOLYTIC DEGRADATION OF AORTIC
WALL CONNECTIVE TISSUE
Aneurysm formation involves a complex process of
destruction of the aortic media and supporting lamina
through degradation of elastin and collagen. Experimental
data and studies of human AAAs suggest that matrix met-
alloproteinases (MMPs) and other proteases, derived from
macrophages and aortic smooth muscle cells, are secreted
into the extracellular matrix and are integral to aneurysm
formation (Table I).3,5 MMPs are also prominent in a
number of pathologic conditions, eg, tumor metastasis and
various rheumatologic and orthopedic disorders. Fluctua-
tion in MMP expression and activity occurs during normal
physiologic aortic wall remodeling. However, in AAAs,
MMP activation favors collagen and elastin degradation.1
Interstitial collagen dissolution accompanies increased ex-
pression of collagenases MMP-1 and MMP-13 in AAAs in
humans. Elastases MMP-2 (gelatinase A), MMP-9 (gelati-
nase B), and MMP-12 (macrophage elastase) are also in-
creased in aneurysmal aortic tissue. MMP-12 is highly
expressed along the proximal leading edge of AAAs in
humans, and may be important in aneurysm initiation.
High concentrations of the constitutive enzyme MMP-2
are found in small aneurysmal aortas, suggesting a role for
MMP-2 during early aneurysm formation. The inducible
enzyme MMP-9 is elevated in aortic tissue and in serum
from patients with AAA compared with patients with aor-
toiliac occlusive disease.8 A critical role for MMP-9 is
supported by the observation that MMP-9 knockout mice
do not form experimental aneurysms. Wild-type bone mar-
row transplantation, however, restores the aneurysm phe-
notype. During AAA formation, the balance of vessel wall
remodeling between MMPs and their inhibitors, tissue
inhibitors of metalloproteinases, favors elastin and collagen
degradation. The mechanisms for initiating and propagat-
ing these proteolytic enzymes in the aorta remain to be
identified.
INFLAMMATION AND IMMUNE RESPONSES
A prominent histologic feature of AAAs is extensive
transmural infiltration by macrophages and lymphocytes. It
is hypothesized that these cells subsequently release a cas-
cade of cytokines that result in activation of many proteases
(Table II). The trigger for influx and migration of leuko-
JOURNAL OF VASCULAR SURGERY
Volume 38, Number 3 Ailawadi, Eliason, and Upchurch 585

Table I. Enzymes documented to be altered in AAA in humans

Enzyme Other names Primary substrate Evidence/origin

Metalloproteinases
MMP-1 Collagenase-1, interstitial Collagen (type I, III) Epithelial, inflammatory, mesenchymal
collagenase
MMP-2 72 kD gelatinase A Collagen (type IV), elastin SMCs, fibroblasts
MMP-3 Stromelysin-1 Collagen
MMP-9 92 kD gelatinase B Elastin, collagen Macrophages, SMCs
MMP-12 Macrophage elastase Elastin Macrophages
MMP-13 Collagenase-3 Collagen (type IV) SMCs
MT-MMP-1 (MMP-14) Activates pro-MMP-2 Membrane-bound protein
TIMP-1 Inhibitor of MMPs AAA wall
TIMP-2 Inhibitor of MMP-2 Expression mildly increased
Cysteine proteases
Cathepsin S Elastin Macrophages, SMCs
Cathepsin K Elastin Macrophages, SMCs
Cathepsin D Not elastin or collagen Increased in AAA wall
Cathepsin L Not elastin or Collagen Increased in AAA wall
Cathepsin H Increased by gene array
Serine proteases
Plasmin Macrophages
Tissue-plasminogen Activates MMPs Protein, expression increased; macrophages
activator
Urokinase-plasminogen Activates MMPs Protein, expression increased; macrophages
activator
AAA, Abdominal aortic aneurysm; MMP, matrix metalloproteinase; SMC, smooth muscle cell; TIMP, tissue inhabitor of metalloproteinase.

creased in the aneurysmal aortic wall. Importantly, these

Table II. Cytokines increased in aortic wall or circulating inflammatory cytokines induce expression and activation of
blood levels in patients with AAA MMPs and tissue inhibitors of MMPs.
An infectious cause has also been suggested in several
Cytokine Effect
reports; as many as 55% of aneurysms demonstrate Chla-
Proinflammatory mydiae pneumoniae by immunohistochemistry. Tambiah
IL-1 ␤ SMC MMP production resulting in and Powell demonstrated experimental aneurysm forma-
increased matrix turnover; circulating tion after periaortic application with live and formalin-
levels higher than control levels
IL-6 Induces MMP expression; increased matrix inactivated C pneumoniae, but not with heat-inactivated C
turnover; circulating levels may correlate pneumoniae antigen.
with aneurysm size The role of reactive oxygen species and antioxidants in
IL-8 Induces MMP expression; increased matrix aneurysm disease has also been an area of interest. Super-
turnover
TNF- ␣ Induces MMP expression; increased matrix oxide (O2–) levels in aneurysmal tissue in human beings is
turnover 2.5-fold higher than adjacent, nonaneurysmal aortic tissue
IFN ␥ Elevated in women with AAAs and with and 10-fold higher than control aorta.10 A greater than
short-term expansion of AAA 50-fold increase in inducible nitric oxide synthase gene
Anti-inflammatory
IL-10 Inhibits inflammatory cytokine production; expression was seen 2 days after infusion of rodent aortas
decreases MMP expression; increases with porcine pancreatic elastase. In contrast, 10 days after
TIMP elastase infusion, expression of superoxide dismutase, a
AAA, Abdominal aortic aneurysm; IL, interleukin; SMC, smooth muscle potent antioxidant, was downregulated more than 20-fold
cell; MMP, matrix metalloproteinase TIMP, tissue inhibitor of metallopro- compared with saline solution–infused control aorta.9
teinase. Thus, an imbalance in gene expression promoting oxidant
stress has been demonstrated in AAAs in humans and in
cytes is unknown, but exposed elastin degradation products experimental AAAs. This pro-oxidant environment has im-
in the aortic wall may serve as a chemotactic agent for portant implications for matrix degradation; in in vitro
infiltrating macrophages. The concept that AAA formation studies reactive oxygen species activated MMPs.12,14
is an autoimmune response is supported by the extensive Reactive oxygen species also influence apoptosis, which
lymphocytic and monocytic infiltrate, primarily in the ad- may be important during AAA formation.6 AAAs histolog-
ventitia, and deposition of immunoglobulin G in the aortic ically demonstrate decreased vascular smooth muscle cell
wall. Xia et al described a new 40 kDa aortic aneurysm– density, contributing to loss of aortic wall structural integ-
associated protein that may be chemotactic.21 Macroph- rity. In situ end-labeling of DNA fragments (TUNEL) has
age-generated and lymphocyte-generated cytokines are in- shown that higher levels of DNA fragmentation, a marker
 JOURNAL OF VASCULAR SURGERY
586 Ailawadi, Eliason, and Upchurch September 2003

Table III. Altered human expression in AAA by gene array*

Gene function Upregulated in AAA Downregulated in AAA

Extracellular matrix degradation Gelatinase B (matrix metalloproteinase 9)

Inflammation Myeloid cell nuclear differentiation antigen
Interleukin-8
CXC chemokine receptor 4
Tumor necrosis factor-␤R
Cellular adhesion ICAM-1 (CD54) Integrin ␣-5
Integrin ␣L (CD11a) Glycoprotein IIIA
Atherosclerosis Apolipoprotein E
Smooth muscle cell contraction Myosin light chain kinase
Intracellular protein degradation and turnover Cathepsin H
Growth factors Platelet-derived growth factor-A Chain
Oncogenes Fli-1
Cell signalling Transcriptional regulator ISGF3, ␥ subunit Ephrin A5
Rho/Rac GEF
*Genes included have at least a fourfold difference in expression when compared with nonaneurysmal aortic tissue.

of apoptosis, can be found in aneurysmal medial smooth
muscle cells. Collectively, these studies provide support for
the hypothesis that oxidative stress is an important compo-
nent in formation and enlargement of AAA through acti-
vation of MMPs and induction of apoptosis within the
aortic wall.
BIOCHEMICAL WALL STRESS
The preferential infrarenal site for AAA formation sug-
gests potential differences in aortic structure, biologic fea-
tures, and stress along the length of the aorta. Structurally,
from proximal to distal along the aorta, the elastin-collagen
ratio decreases; ie, the infrarenal aorta has low levels of
elastin compared with the aortic arch and descending tho-
racic aorta. Further, a decrease in the elastin-collagen ratio
from proximal to distal aorta may be clinically relevant,
because diminished elastin is associated with aortic dilation,
and collagen degradation predisposes to aortic rupture.
Ailawadi et al documented that, in addition to diminished
elastin, the abdominal aorta has increased MMP-9 expres-
sion and activity compared with aortic arch and descending
thoracic aortic segments.
Flow studies have also suggested disordered flow and
an increase in wall tension in the infrarenal aorta.11 Ex vivo
models have documented activation of MMPs as a conse-
quence of these mechanical alterations. Others have sug-
gested that relative tissue hypoxia occurs in the infrarenal
aorta as a discrete vasa vasorum ends near the renal artery
branches. A combination of these factors likely contributes
to the preponderance for aneurysms to form in the infrare-
nal aorta.
Once an AAA has developed, it is likely that increased
wall stress is important in accelerating dilation and increas-
ing the risk for rupture. ␤-Blockers reduce wall stress, and it
has been suggested that they protect against continued
aneurysm dilation and rupture in animal models. In human
trials, however, this observation has not been convincingly
reproduced.
In an attempt to better understand the relationship
between wall stress and risk for aneurysm rupture, several
groups have used sophisticated, computer-based three-
dimensional “finite element analysis” of the aorta. Studies
by Vorp, Fillinger, and others have made significant contri-
butions in this field. In one study, analysis of computed
geometric factors suggested that aneurysm volume, rather
than simply AAA diameter, was the best indicator of peak
wall stress.13 From a biomechanical standpoint, the effect
of intraluminal thrombus may serve to lower aortic wall
stress.18 Furthermore, ruptured or symptomatic AAAs had
significantly higher peak wall stress compared with diame-
ter-matched asymptomatic AAAs.4 This is a dynamic pro-
cess with multiple variables, but recent advances in this area
may improve risk stratification and subsequent decision-
making as to which patients should be considered surgical
candidates.
MOLECULAR GENETICS
Certain phenotypes have been associated with AAAs.
For example, the Hp-2-1 haptoglobin phenotype and de-
ficiencies in ␣1-antitrypsin are associated with aneurysm
formation. Patients with Rh-negative blood type have de-
creased frequency of AAA, whereas those with MN or
Kell-positive blood groups have increased frequency. Cur-
rently no single genetic defect or polymorphism has been
identified as a common denominator for AAA. However,
familial clustering and a common HLA subtype suggest
both a genetic and an immunologic role in the pathogen-
esis of AAA. Patients with affected siblings are at substan-
tially increased risk for AAA. Gene microarray has provided
information regarding altered gene expression in patients
with AAA (Table III).17 Specific polymorphisms have also
been linked to AAA formation (Table IV). Genetic screen-
ing of patients predictably at high risk for AAA develop-
ment will likely become a reality in the future.
PROPOSED MECHANISM
A combination of factors, eg, localized hemodynamic
stress, fragmented medial proteins, and genetic predisposi-
tion, through an unknown immunologic mechanism, likely
attracts inflammatory cells into the aortic wall (Figure).
JOURNAL OF VASCULAR SURGERY
Volume 38, Number 3
Table IV. Polymorphisms associated with AAA
Polymorphism
Heme oxygenase-1 gene promoter
Angiotensin converting enzyme gene
Apolipoprotein E gene
Plasminogen activator inhibitor-1
gene promoter
TIMP-1 and TIMP-2 genes
Endothelial nitric oxide synthase gene
HLA-DR B1 gene
AAA, Abdominal aortic aneurysm; TIMP, tissue inhibitor of metallsproteinase; HLA, human leukocyte antigen.
Proposed mechanism of aortic aneurysm formation. IEL, Internal elastic lamina; EEL, external elastic lamina. (Courtesy
of B. S. Knipp, MS, University of Michigan Medical School, Ann Arbor, Mich.)
Ailawadi, Eliason, and Upchurch 587
Patients with AAAs Patients without AAAs
Homozygous or heterozygous for less than Homozygous or heterozygous for less than
25 GT repeats, 41% 25 GT repeats, 59%
Normotension Normotensive control patients
DD genotype frequency, 70% DD genotype frequency, 25%
II genotype frequency, 5% II genotype frequency, 32%
Hypertension
DD genotype frequency, 32%
II genotype frequency, 21%
E3E3 genotype: expansion rate, 2.1 mm/y
E3E4 genotype: expansion rate, 1.3 mm/y
E2E3 genotype: expansion rate, 3.1 mm/y
E2E4 genotype: expansion rate, 4.2 mm/y
Familial AAA Healthy control subjects
4G4G geneotype frequency, 20% 4G4G geneotype frequency, 35%
5G5G geneotype frequency, 26% 5G5G geneotype frequency, 13%
Nonfamilial AAA
4G4G geneotype frequency, 38%
5G5G geneotype frequency, 14%
Female TIMP-1 nt 434 Female TIMP-1 nt 434
C allele frequency, 62% C allele frequency, 27%
T allele frequency, 38% T allele frequency, 73%
Male TIMP-2 nt 573 Male TIMP-2 nt 573
G allele frequency, 91% G allele frequency, 79%
A allele frequency, 9% A allele frequency, 21%
Patients with AAA requiring operation Healthy control subjects
5 repeat intron 4 allele frequency, 79% 5 repeat intron 4 allele frequency, 90%
4 repeat intron 4 allele frequency, 21% 4 repeat intron 4 allele frequency, 10%
Patients with AAA under observation
5 repeat intron 4 allele frequency, 96%
4 repeat intron 4 allele frequency, 4%
Patients with inflammatory AAAs Healthy control subjects
HLA-DR B1*15 allele frequency, 47% HLA-DR B1*15 allele frequency, 27%
HLA-DR B1*0404 allele frequency, 14% HLA-DR B1*0404 allele frequency, 3%

588 Ailawadi, Eliason, and Upchurch
Inflammatory cells then release chemokines, cytokines, and
reactive oxygen species, resulting in further influx of leuko-
cytes, with subsequent expression and activation of induc-
ible and constitutive proteases, notably MMPs. These pro-
teases result in medial degradation and aneurysmal dilation,
with ongoing remodeling. Increased wall stress enhances
proteolysis and progressive aneurysm dilation, with even-
tual aortic rupture if untreated.
FUTURE THERAPIES
Initial clinical observations followed by intense basic
science and translational research on the underlying patho-
genesis of aortic aneurysms have underscored the complex-
ity of this inflammatory process. Progress is being made on
many fronts. For example, a better understanding of which
AAAs are at risk for rupture from increased wall stress is
being developed. In addition, ongoing studies examining
the genetic basis for aneurysm disease will shed further light
on the interactions between the aortic wall and circulating
factors important in aneurysm development.
To date, surgical and endovascular therapy for end-
stage aortic aneurysm disease is all we have to offer the
patient with an AAA. Risk factor modification, eg, cessation
of cigarette smoking and control of hypertension, may help
to slow AAA growth and reduce coronary deaths. How-
ever, strategies aimed at determining who is at risk for
development of an aortic aneurysm and at slowing the
growth of small AAAs once present are needed. Clinical
trials using antiproteinases and anti-inflammatory agents
should be performed.
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Submitted Feb 5, 2003; accepted Feb 12, 2003.