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Page 6 of 13 Pisano et al. Vessel Plus 2020;4:33 I http://dx.doi.org/10.20517/2574-1209.2020.21

MMP-9 expression induced an increase in proteolysis in TAA and TAD as compared to the normal aorta.
Finally, the TLR-4-mediated pathways seems to influence the activity of two important genes involved in
[51]
the onset and progression of TAA: transforming growth factor-β (TGF-β) and Notch [52,53] . Different roles
of TGF-β pathways in tissue remodeling mechanisms have been reported in both syndromic and sporadic
TAA. The activation of TGF-β results in an increase in extracellular matrix degradation through MMPs
activation and multiple cytokines upregulation including interleukin-10. Additionally, a loss of function
of the TGF-β receptors (TGFBR1 and TGFBR2) has been associated with both familial syndromic and
non-syndromic TAAs. Furthermore, mutations in Notch gene homolog 1 (Notch1) and Notch1 pathway,
typically associated to TAA patients with BAV, seem to regulate TGF-β cascade. In the aorta, the Notch
pathway appears to regulate the differentiation of vascular smooth muscle cells, the most representative
[54]
cells involved in aneurysmatic pathology. Finally, a very recent study revealed the important role of the
phosphodiesterase 5A (PDE5) gene mutation in human aorta and thoracic aortic aneurysms. Affected
aortas showed lower levels of all the PDE5A isoforms compared to control aortas. Because PDE5 is
expressed early during human aorta development, the study revealed an association between PDE5 gene
mutation and anomalous aortic development.

Impact of histopathological changes in thoracic aortic diseases and genetic biomarkers of risk
One of the most important aspect to consider in order to optimize surgical indications in TAD is the
severity of medial degeneration of the aortic media and, consequently, the fragility of the aortic wall.
Previously, we observed that the severity of aortic media degeneration in TAD and TAAs are not related
to the diameter of the aneurysm [55-58] . In atherosclerotic degenerative aneurysms (ADA), the grade of
medial degenerative lesions was balanced to the grade of substitutive medial fibrosis. In contrast, in non-
atherosclerotic degenerative aneurysm (NADA) and TAD, medial fibrosis was absent or of grade I. The
relative absence of restorative fibrosis should predispose patients to aortic rupture. In particular, our study
showed that TAD has the same histological and immunohistochemical features as NADA phenotype
III: elevated medial cystic degeneration without replacement fibrosis, with plurifocal medial apoptosis,
and strong collagenase concentration. Additionally, NADA phenotype III showed a very fragile aortic
wall at the time of the operation. The morphological identity of the medial lesions observed both in
NADA phenotype III and in the samples of patients with TAD, could be considered the precursor - and
consequently the optimal biomarker - of the dissection, regardless of the diameter of the aneurysm or valve
disorder. This evidence agree with recent studies that showed that up-regulation of metalloproteinases,
related to inflammatory processes or genetic aspects, might affect the formation of TAA and TADs .
[59]
In order to identify patients with small to moderate sized aneurysms and at high risk of developing TAD,
[55]
Balistreri et al. investigated the genetic biomarkers specific for TAA phenotype III. Investigations
were made into the potential role of 10 common and functional single nucleotide polymorphisms
(SNPs) of the following genes: CCR5 (C-C chemokine receptor 5), TLR4 (toll like receptor 4), MMP-9
(metalloproteinase-9), MMP-2 (metalloproteinase-2), ACE (angiotensin-converting enzyme), and eNOS
(endothelial nitric oxide synthase). Indeed, highly significant associations were observed between -786T/
C eNOS, D/I ACE, and -735C/T MMP-2 SNPs and the risk of TAD. The presence of these genotypes may
induce the development of this disease through different mechanisms [Figure 5]. A relationship between
ACE gene SNPs and arterial hypertension has been demonstrated in different populations. At the same
time, chronic systemic hypertension is considered to be the most common predisposing factor for TAD,
with unfavorable effects on the vascular system such as cellular apoptosis, the production of reactive
oxygen species, and vascular matrix MMP synthesis (particularly of MMP-2 and -9). In addition, it is
known that molecules such as NO are involved in several pathways for the maintenance and regulation
of a healthy intimal endothelium. Different SNPs of the eNOS enzyme have been found to vary in the
expression and tissue levels of NO. In particular, -786 T/C eNOS reduced the transcriptional activity by
around 50%, leading to a reduction in eNOS tissue endothelium levels that may result in reduced NO