Page 27 - GTM-2-1

Global Translational Medicine Stem cells in aortic aneurysm

2. Mechanism of AA formation maintained by TGF-β signaling pathway . Decrease of
[15]
VSMC contractile phenotype markers (such as SM22-α
2.1. An overview of AA and SMα-actin) expression but increase of inflammatory
AA is a permanent, local dilation of the aortic wall, proteins release was observed in AAA tissues, which
usually >50% of the normal diameter of the aorta. AA is contributed to the AAA development . Multi-lineage
[2]
clinically termed according to the location. The one above tracing of VSMCs and their progeny in a mouse AA model
the diaphragm in the upper aortic segment is defined as showed clonal expansion and the presence of phagocytic
thoracic AA (TAA) and the abdominal AA (AAA) is markers CD68 and lysosomal-associated membrane
[4]
mainly located below the renal arteries . protein 2 (LAMP2). Thus, this is the activation of a switch
[5]
[16]
Epidemiological studies have shown that male, elderly of VSMC to the phagocyte-like phenotype in AA .
patients, smoking, hypertension, and atherosclerotic The ECM mainly produced by VSMCs in the arterial wall
cardiovascular disease are risk factors for AAA . TAA is composed of elastin, collagen, and proteoglycans . The
[6]
[17]
has a lower prevalence than AAA and is divided into three role of ECM degradation in AAA is mainly reflected in the
types: Syndromic, familial non-syndromic, and sporadic . destruction of collagen and elastin and the accumulation
[7]
[18]
Syndromic TAA usually includes Marfan syndrome (Fbn1 of abnormal proteoglycans , which is facilitated by the
[19]
mutation), Ehlers-Danlos syndrome (collagen or collagen formation of AAA. The ECM is primarily degraded by
processing enzymes mutation) or Loeys Dietz syndrome proteolytic enzymes, including matrix metalloproteinases
(transforming growth factor beta [TGF-β] receptor mutation) (MMPs) and cysteine cathepsins . Under conditions of
[20]
and so on . About 20% of TAA patients can be attributed to aortic inflammation, MMPs can be increasingly secreted
[1]
specific genetic variants, which are familial non-syndromic by neutrophils and macrophages. Among them, MMP1,
TAA. Among them, autosomal dominant inheritance MMP2, MMP9, MMP13, and MT1-MMP can destroy
is the most common type . The risk factors of sporadic collagen, and MMP2, MMP9, and MMP12 can destroy
[7]
TAA are similar to AAA, such as smoking, hypertension, elastin, leading to aortic ECM degradation and aneurysm
atherosclerotic cardiovascular disease, and so on . generation Cathepsin S/K/L can promote the formation
[6]
[21]
Most AAAs expand slowly without symptoms. For every of AAA, and a lack of that may reduce the inflammatory
0.5 cm increase in AAA diameter, the growth rate increases response in AAA lesions [20,22,23] .
by 0.5 mm/year and the rupture rate doubles . The growth Oxidative stress refers to an imbalance in the production
[8]
rate of TAA is faster than that of AAA . The mortality and elimination of ROS. An elevation of ROS level has been
[9]
rate after the rupture of AA is as high as 60 – 90% . As found in the tissues of AAA patients , and it is believed
[10]
[24]
a result, it is essential to study the pathogenic mechanism that ROS can upregulate proteolytic enzymes such as MMP
and effective treatments of the AA. to induce ECM degradation and promote VSMC damage
[25]
Some of the AA, especially TAA, enlarge over time, as well . The principle is that TGF-β signaling upregulates
until a tear forms in the intimal layer of the aortic wall Nox4 to promote ROS production . Compared with
[26]
typically above the sinotubular junction that leads to aortic thick-walled AA, the expression of oxidative stress and
dissection (AD) . AD is a serious condition characterized proteolytic enzyme is significantly increased in thin-walled
[11]
by a split of the different layers of the aorta wall and a rush AA, which is considered to be the primary risk factor for
of blood through the dissection. It happens suddenly and AAA rupture, indicating the importance of oxidative stress
[12]
causes nearly half of patients to die from aortic rupture . in the AAA enhancement [26,27] .
To some extent, there are several similarities between the From the above, it can be inferred that the apoptosis of
formation mechanism of AA and AD. VSMC and the degradation of ECM are inseparable from
2.2. AAA the vascular inflammatory response, which proves the
importance of inflammation in the pathogenesis of AA. It
The mechanisms of AAA formation comprise VSMC injury has been proven that inflammation is a common feature
and apoptosis, extracellular matrix (ECM) degradation, of AAA lesions, which is manifested by the widespread
oxidative stress, and vascular inflammation . presence of inflammatory molecules, accumulation
[13]
VSMCs, as the major cell type in the medial aorta, and infiltration of inflammatory cells, and changes in
play a key role in providing structural support, regulating signal transduction . Polarized macrophages with a
[28]
vascular tone, and aiding in vascular remodeling . Studies pro-inflammatory phenotype (M1) aggregated in AAA
[14]
have shown that the damage of VSMC in AAA patients tissue, triggering tissue degradation and promoting the
is mainly manifested in contractibility dysfunction. aneurysm development in the CaCl model . In contrast,
[29]
2
Normally, most VSMCs exhibit a contractile phenotype anti-inflammatory phenotype (M2) macrophages are
Volume 2 Issue 1 (2023) 2 https://doi.org/10.36922/gtm.v2i1.241