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Endothelial cell dysfunction has also been linked to TAA pathology, but its precise role is less extensively studied. Decreased endothelial proliferation and differentiation, as well as altered endothelial expression of contractile apparatus or ECM
proteins, have been observed in TAA patients. As endothelial cells inuence VSMC
differentiation, they may contribute VSMC dysfunction and, thus, to aortic wall
deterioration and TAA formation [18].
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13.4 Syndromic Thoracic Aortic Aneurysm Presentations
Patients can present with isolated TAA or syndromic TAA, with the latter being
most thoroughly studied over the years. The specic combination of the multisystemic phenotypic traits in syndrome TAA patients, often already present in early
childhood, facilitates early establishment of a diagnosis [19]. Most syndromic TAA
presentations are inherited in an autosomal dominant manner, with the exception of
BGN and FLNA mutations which are inherited in an X-linked manner [19] and
SLC2A10 and EFEMP2 mutations which segregate in an autosomal recessive man-
ner [20, 21].
13.4.1 Marfan Syndrome
In 1896, Antoine-Bernard Marfan rst described Marfan syndrome (MFS), which
is now known as the most common (circa 1:5000) and best studied syndromic
TAA condition. Multiple organ systems are affected, i.e. the skeletal, ocular, skin
and cardiovascular system. The most frequent musculoskeletal manifestations
are skeletal overgrowth of the long bones, arachnodactyly, pectus deformities,
joint laxity and facial features. Myopia and ectopia lentis are characteristic ocular features, while striae are a typical skin symptom. The cardiovascular manifestations (i.e. TAA(D) and mitral valve disease), however, pose the greatest threat.
In MFS, aortic aneurysms typically occur at the sinus of Valsalva and the proximal aorta [22, 23].
MFS has an autosomal dominant inheritance pattern and is caused by mutations
in the FBN1 gene [24]. FBN1 encodes a large extracellular glycoprotein, brillin-1,
that is secreted by endothelial cells and VSMCs. It forms complex microbrils,
providing elasticity and structural support to the aortic wall, but also regulates the
bioavailability and activity of growth factors. About 1850 different FBN1 mutations, which are widely spread over the entire gene, have been described to date
(http://www.umd.be/FBN1/), explaining approximately 95% of MFS cases. FBN1
mutations lead to impaired protein synthesis, secretion and loss of the microbrillar
architecture, compromising tissue homeostasis and strength [25].
FBN1-related structural tissue weakness can not solely explain all MFS clinical
manifestations (e.g. skeletal overgrowth, craniofacial dysmorphism and skeletal muscle
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hypoplasia). Using a MFS mouse model that fully reproduces the MFS phenotype, an
important additional role for dysregulated TGF-β (transforming growth factor-β) signaling in the pathophysiology of MFS was shown [26, 27]. Under normal physiological
circumstances, brillin-1 is capable of binding TGF-β ligands that are complexed
within a large latent complex [22, 23]. Mutant brillin-1 excessively releases these
TGF-β ligands, thus increasing the amount of bioavailable TGF-β and TGF-β signaling.
M. H. A. M. Perik et al.
13.4.2 Loeys-Dietz Syndrome
Loeys-Dietz syndrome [28] has a signicant clinical overlap with other connective
tissue disorders such as MFS, Shprintzen-Goldberg syndrome and Meester-Loeys
syndrome. Hypertelorism, craniosynostosis, bid uvula, cleft palate and arterial tortuosity, however, are discriminative LDS features. Moreover, with respect to the
aortic phenotype, LDS patients are more severely affected with dissections and ruptures occurring at smaller aortic diameters, at younger ages and throughout the arterial tree [29, 30]. Dissection or rupture has been reported in children as young as
3months [31], emphasizing the need for early cardiovascular screening in cases
where LDS is suspected.
Six autosomal dominant LDS genes have been identied so far, i.e. TGFBR1,
TGFBR2, SMAD3, TGFB2, TGFB3 and SMAD2, which are now implicated as the
causes of LDS types 1–6 [32–35] (Table13.1). They encode cytokines, receptors or
intracellular effectors of the TGF-β pathway. Upon the discovery of causal mutations
in TGFBR1 and TGFBR2, the initial LDS classication was based on the presence or
absence of outward phenotypic appearance (e.g. cleft palate, craniosynostosis, hypertelorism). Dysmorphic patients who showed prominent craniofacial traits hinted
towards a LDS1 subtype, while EDS-vascular traits were directing towards LDS2.
Since the discovery of the other currently known genes, classication and diagnosis
of the different subtypes has become based upon the underlying gene defect [19].
In all LDS subtypes, the mutation has been shown to cause loss-of-function in
genes involved in the TGF-β pathway. This suggest that the primary event in LDS is
a lack of, or reduced, TGF-β signaling. However, subsequent biochemical analysis
of aortic tissues revealed nuclear accumulation of pSMAD2/3 and upregulation of
prototypical TGF-β target genes such as MMP2, MMP9, COL3A1 and CTGF,
revealing paradoxically enhanced TGF-β signaling [36].
13.4.3 Shprintzen-Goldberg Syndrome
Shprintzen-Goldberg syndrome (SGS) is a very rare autosomal dominant connective tissue disorder that was rst recognized as a separate clinical entity in 1982. The
SGS phenotype involves the craniofacial, neurological, skeletal and cardiovascular
systems and has signicant overlap with MFS, LDS and vascular Ehlers-Danlos
syndrome. The most discriminative features of SGS are craniosynostosis and
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developmental delay with intellectual disability. Although the cardiovascular manifestations in SGS are not as severe as in LDS, complications such as progressive
aortic root dilation have been reported as a cause of death [37].
SGS is caused by mutations in SKI, which encodes a TGF-β repressor [38]. Most
SGS patients carry a de novo mutation, either in the N-terminal SMAD2/3 binding
domain (73%) or the Dachshund-homology domain. These domains are important
for binding of SKI with SMADs and other cofactors, necessary for the recruitment
of transcriptional co-regulators. Under normal conditions SKI binds the MH2
domain of SMAD2/3, displacing the transcriptional activator p300. This SKISMAD complex alters the local chromatin environment so that TGF-β signaling is
inhibited. Mutations in SKI render it unable to properly bind the SMAD proteins,
resulting in loss of inhibitory feedback of the TGF-β signalling pathway. Although
in depth understanding of TGF-β signalling in is currently lacking, the clear involvement of counter regulatory or compensatory TGF-β signalling events contributes
greatly to the pathophysiological understanding of TAA development [23, 39].
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13.4.4 Meester-Loeys Syndrome
Defects in the X-linked BGN gene cause a disorder that strongly overlaps with LDS
and MFS, and presents with hypertelorism, bid uvula, early-onset aortic dilatations (as young as 1year) and dissections, pectus deformities, joint hypermobility,
and striae. Findings which are more characteristic for Meester-Loeys syndrome
(MLS) are ventricular dilatation on brain imaging, gingival hypertrophy, mild skeletal dysplasia with platyspondyly (attened and widened vertebral bodies), phalangeal dysplasia and dysplastic epiphyses of the long bones [40]. Male mutation
carriers are more severely affected than females, demonstrated by an early onset of
cardiovascular manifestations in males and a variable phenotype in females, ranging from unaffected through aortic root dilatation to death due to aortic dissection.
BGN encodes for the biglycan protein, which belongs to the small leucine-rich
proteoglycan class I proteins and has both structural and functional properties in the
vascular wall. Biglycan interacts with multiple ECM proteins, including collagen
type I/II/III/VI, elastin and microbrils [40, 41], and is thus involved in ECM
assembly. Biglycan also interacts with several growth factors and cytokines, including TGF-β, in order to regulate cell proliferation, migration and differentiation. In
the aortic wall of MLS patients, a lack of biglycan has been shown to be associated
with increased TGF-β signaling [40].
13.4.5 Vascular Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome (EDS) refers to a group of connective tissue disorders that
is most prominently characterized by skin (hyperextensibility, translucency, easy
bruising) and ligament/joint (hypermobility) manifestations. A subset of EDS cases
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present with aortic aneurysmal disease. Aneurysms are most prevalent in vascular
EDS (vEDS, EDS type IV), which has the worst prognosis amongst all EDS subtypes and is one of the most severe connective tissue diseases [30].
vEDS represents approximately 5% of EDS cases, and has an estimated prevalence between 1:50000 and 1:100000. A high mortality rate is seen in young patients
due to early rupture of arteries (with or without aneurysms) and hollow organs, usually during the third decade of life [42]. In contrast to MFS, LDS, MLS and SGS,
mostly medium-sized abdominal vessels such as renal, iliac, femoral, mesenteric
and hepatic arteries are involved, but aortic involvement is also regularly reported.
Owing to signicant soft tissue fragility, surgical intervention in vEDS patients is
associated with severe complications and relatively high mortality rates.
vEDS is inherited in an autosomal dominant manner and is caused by mutations
in the COL3A1 gene [43]. Several dozen mutations of COL3A1 have been identied
to date, all leading to structurally defective collagen III pro-α1-chains. The mutation
spectrum encompasses mostly glycine-affecting missense mutations, splice site
mutations and (multi)-exon deletions. Mutations causing COL3A1 haploinsufciency lead to milder phenotypes [43].
Occasionally, mutations in COL1A1 and COL5A1, i.e. respectively arthrochalasia (pathological loosening of joints) and classical EDS genes, have been found in
patients who are clinically diagnosed with aneurysmal phenotypes [44, 45]. These
genes encode collagens, which upon formation of homo- or heterotrimeric brils
produce the ECM of internal organs and skin, providing tissue tensile strength.
M. H. A. M. Perik et al.
13.4.6 Periventricular Nodular Heterotopia Type 1
Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder that
often comes with difcult-to-treat seizures. It can occur with or without EDS-like
connective tissue anomalies, including TAA. The condition is caused by loss- offunction mutations in the X-linked FLNA gene, encoding the cytoskeletal component lamin A that connects the VSMC contractile apparatus to cell membranes and
the ECM [46, 47]. Recently aortic dissections have also been reported in FLNA
patients [47].
13.4.7 Arterial Tortuosity Syndrome
The main characteristics of arterial tortuosity syndrome (ATS) are the elongation as
well as increased twisting and turning of major arteries [48], including the thoracic
and abdominal aorta. Additionally, ATS can present with stenosis, dilatation or dissection of the aorta and/or pulmonary arteries, craniofacial dysmorphism, a soft and
doughy skin, marfanoid skeletal ndings (e.g. scoliosis, joint laxity and arachnodactyly), hypertelorism and hypotonia [49]. Compared to LDS patients, ATSpatients
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have more generalized tortuosity of the major blood vessels. ATS clinical presentation and severity can be highly variable, ranging from early mortality during childhood to limited features at advanced age [48].
ATS is a rare syndrome that is caused by autosomal recessive loss-of function
variants in the SLC2A10 gene [20]. SLC2A10 encodes the facilitative glucose transporter GLUT10. Abnormal transport of GLUT10 substrates hinders mature glycoprotein and proteoglycan production, leading to abnormal ECM deposition and loss
of vascular wall integrity, arterial tortuosity and aneurysm development.
Downregulation of decorin, a proteoglycan and TGF-β inhibitor, has been observed
in VSMCs and broblasts of ATS patients, suggesting TGF-β involvement in the
pathogenesis of ATS [20].
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13.4.8 Autosomal Recessive Cutis Laxa Type 1
Cutis laxa is a connective tissue disorder characterized by inelastic and loose skin.
Although autosomal recessive cutis laxa type 1 (ACRL1) is categorized as a cutis
laxa subtype, this condition is mainly characterized by vascular anomalies and, less
commonly, lung emphysema and diverticula of the urinary and gastrointestinal tract
[50, 51]. The predominant vascular ndings are aortic aneurysms as well as arterial
tortuosity and stenosis [52]. ARCL1 is caused by autosomal recessive mutations in
the EFEMP2 gene [53]. EFEMP2 codes for bulin-4, an ECM protein that is
involved in elastic bre formation.
13.5 Non-syndromic Disorders
Familial TAAD (FTAAD) refers to non-syndromic TAAD with a positive family
history. In the absence of a family history, mutations in FTAAD genes can be suspected when aneurysms are detected in young patients, or occur in the absence of
other known risk factors such as hypertension or atherosclerosis. FTAAD inherits in
an autosomal dominant manner and typically comes with reduced penetrance.
ACTA2 was the rst described FTAAD gene. Mutations in this gene account for
a remarkable 14–21% of FTAAD cases, but are associated with low penetrance
(~50%). In addition to TAAD, stroke, premature coronary artery disease, AAA,
bicuspid aortic valve, patent ductus arteriosus, livedo reticularis, and iris occule
are common ACTA2-related symptoms [54, 55]. ACTA2 encodes aortic smooth
muscle actin, a major constituent of the contractile apparatus that is involved in
artery shape maintenance.
MYH11 mutations are found in less than 2% of FTAAD patients [56], most com-
monly in pedigrees in which both TAAD and patent ductus arteriosus, i.e. failed
closure of the arterial shunt between the aorta and the pulmonary artery, coincide.
Also in this case, reduced penetrance is frequently observed. Additionally, a
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M. H. A. M. Perik et al.
considerable number of MYH11 variants of unknown signicance have been identied. MYH11 encodes smooth muscle myosin heavy chain, which is an important
constituent of the thick contractile laments in VSMCs.
Loss-of-function mutations in the short isoform (130kDa) of MYLK explain less
than 1% of FTAAD patients. In most mutation carriers, little or even no aortic
enlargement occurs prior to dissection. Hypertension, however, has been suggested
to be an important dissection-provoking factor in MYLK cases. MYLK encodes
smooth muscle myosin light chain kinase (MLCK) which initiates VSMC contraction upon interaction with calcium-calmodulin complexes [57].
Only one single PRKG1 mutation, p.Arg177Gln (where a single base mutation
has changed arginine to glutamine), has been reported to cause FTAAD to date [58].
Besides aortic aneurysms and dissections at young age (15–51 years), this fully
penetrant gain-of-function mutation is associated with tortuosity and hypertension.
PRKG1 encodes for a type I cGMP-dependent protein kinase, which dephosphorylates the regulatory light chains (RLCs) of VSMCs. The p.Arg177Gln mutation
leads to constitutive activation of the enzyme and, hence, to a pathological decrease
in RLC phosphorylation.
Mutations in MAT2A and FOXE3 have also been linked to FTAAD [28, 59]. To
date, only one extended family harbouring a MAT2A mutation has been reported
[59]. TAAD penetrance is low, with only seven out of 15 mutation carriers >30years
of age being affected. Therefore, it has been suggested that TAAD development in
individuals with MAT2A loss-of-function variants might require co-occurrence with
another genetic or environmental TAAD risk factor. Since some affected mutation
carriers also had a bicuspid aortic valve (BAV), and thus BAV might be considered
such a provocative factor. Little is known about the precise role of the protein
encoded by MAT2A, (methionine adenosyltransferase II), in the cardiovascular system.
FTAAD-causing FOXE3 mutations specically affect amino acids at the
C-terminal end of the forkhead DNA-binding domain. Dominant FOXE3 mutations
either at or outside the N-terminal domain, however, cause ocular disease [
60].
Remarkably, so far only male FOXE3 mutation carriers have been found to be
affected by TAA.While the role of the transcription factor FOXE3 in the cardiovascular system has been poorly studied, some experiments point towards FOXE3
involvement in VSMC development and differentiation.
MFAP5 haploinsufciency (see Glossary) is another genetic cause of FTAAD
[61]. MFAP5 encodes an ECM component called microbrillar-associated protein 5
(also known as microbril-associated glycoprotein 2 (MAGP2)), which localizes to
brillin-containing microbrils and interacts also with growth factors such as
TGF-β and bone morphogenetic protein (BMP). As for other FTAAD genes, penetrance is less than 50% [61]. Mild systemic features and lone paroxysmal atrial
brillation have also been observed in some carriers but it remains to be conrmed
that these are truly related to MFAP5 deciency.
BAV is characterized by an aortic valve with two leaets instead of the normal
three and is the most common congenital heart defect with a prevalence of 1%. In
about 20% of BAV patients, dilatation of the aortic root or ascending aorta occurs
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[62]. Previous studies have linked mutations in NOTCH1 [61], SMAD6 [62] and
ROBO4 [63] to BAV.However, the majority of BAV and BAV/TAA genetics remains
obscure. 15% of the LOX mutation carriers also presented BAV in addition to TAA
[64]. LOX codes for protein lysine 6 oxidase, (lysyl oxidase), an extracellular copper enzyme that initiates crosslinking of collagen and elastin [64].
Finally, mild mutations in several syndromic TAA genes (e.g. TGFBR2, FBN1,
SMAD3, TGFB2) have been found in TAA patients without outward features.
Therefore, the distinction between syndromic and non-syndromic causes of TAA is
somewhat articial.
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13.6 Pathogenesis ofThoracic Aortic Aneurysm/Dissection
Summarizing the current knowledge on the genetic basis of TAA(D) (Table13.1), it
can be stated that TAAD is caused by defects in genes coding for proteins belonging
to three overlapping and interacting functional groups, depicted in Fig.13.1. These
groups encompass the structural integrity and/or homeostasis of the ECM, the regulatory function of VSMCs in the aortic wall and the TGF-β pathway [19, 41]. Fibres
of the ECM are able to connect with VSMCs in the aortic wall in order to form a
matrix-cell complex and synchronize the mechanical properties of the aortic wall’s
components. Abnormal ECM composition due to mutations in genes encoding for
structural proteins (e.g. Fibrillin-1), may lead to loss of physical VSMC-ECM interaction as well as increased MMP expression and subsequent collagen and elastin
degradation. VSMCs will react on these changes by switching from a normal contractile phenotype into a pathogenic synthetic phenotype, which promotes VSMC
proliferation and migration. On the other hand, mutations in the genes encoding for
the contractile apparatus of the VSMCs can disrupt the contractile machinery, also
favouring the synthetic VSMC phenotype and reducing vascular wall elasticity due
to improper contractility and increased expression of ECM components or MMPs.
The TGF-β pathway mediates the expression levels of various proteins involved in
ECM homeostasis and is implicated in aortic contractile-to-synthetic VSMC phenotypic switching [41].
13.6.1 Structural Integrity oftheECM
Elastic and collagen bres account for 60% of the aorta’s bulk dry weight and are
indispensable for its normal physiological compliance. Assembly of these bres
depends on the proper formation of intramolecular and intermolecular crosslinks.
To date, numerous genes encoding components of the ECM (e.g. FBN1, MFAP5,
COL3A1, BGN, EFEMP2, LOX) have been associated with TAAD development.
Mutations in these genes alter normal elastin or collagen bre formation and stability as well as crosslinking. Elastic bres consist of microbrils and elastin polymers
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Fig. 13.1 Overview of the genetic basis of thoracic aortic aneurysm and dissection related disorders. Three interacting functional groups can be distinguished in which gene defects can lead to
TAA(D)s: structural integrity of the ECM, the VSMC contractile unit and the TGF-β pathway. (a)
Structural integrity and/or homeostasis of the extracellular matrix can be disrupted by mutations in
genes such as brilin-1 (FBN1), biglycan (BGN), elastin (ELN), bulin-4 (FBLN4), lysyl oxidase
(LOX), collagens (COL3A1, COL5A1, COL1A1) and microbrillar-associated protein (MFAP5).
(b) Mutations in genes involved in the regulatory function of VSMCs, i.e. actin alpha-2 smooth
muscle (ACTA2), lamin A (FLNA), myosin heavy chain 11 (MYH11), myosin light chain kinase
(MYLK) and protein kinase cGMP-dependent 1 (PRKG1), reduce the capability to withstand
mechanical forces during contraction. (c) The TGF-β signalling pathway can be divided in the noncanonical (left) and canonical (right) pathway (see Glossary). Multiple genes related to the latter
are involved in aneurysm pathogenesis, including TGF-β ligands 2 and 3 (TGFB2/3), TGF-β
receptors 1 and 2 (TGFBR1/2) and mothers against decapentaplegic homolog 2, 3 and 4
(SMAD2/3/4), in which loss of function mutations paradoxically lead to increased TGF-β signalling. In addition, SKI proto- oncogene (SKI) and SMAD6 inhibit the signalling pathway by preventing nuclear translocation and SMAD2/3-SMAD4 complex forming, respectively. Proteins
encoded by genes known to cause TAA(D) are indicated with a red asterix. LTBP latent transforming growth factor β-binding protein, LAP latency associated peptide domain, VSMC vascular
smooth muscle cell. (Adapted from Verstraeten etal., 2017 [4])
M. H. A. M. Perik et al.
that give, respectively, strength and elasticity to the vascular wall. Microbrils are
formed by head-to-tail longitudinal polymerization and lateral binding of brillin-1
and brillin-2 molecules [65]. In MFS patients, mutant brillin- 1 is erroneously
incorporated into microbrils or abnormally expressed, leading to disruption of the
elastin-contractile unit. To form elastin polymers, tropoelastin (ELN) binds to bulin-4/5 complexes associated with lysyl oxidase (LOX) and LOX-like proteins [65].
Furthermore, structural integrity loss has also been associated with MFAP5 muta-
tions, disrupting the adherence of smooth muscle cells to elastin bers. In addition,
MAGP2 is able to bind reversibly to multiple members of the TGF-β/BMP
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signaling pathway, such as TGF-β1/2 and BMP, and thereby altering signaling
intensities.
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13.6.2 Regulation oftheVSMC Contractile Unit
Within the aortic wall, VSMCs are embedded in the ECM and are circumferentially
arranged in multiple layers in between the elastic lamina of the aortic wall. VSMCs
exhibit signicant plasticity in order to regulate the lumen diameter of the aorta,
and thus blood pressure, by regulation of their contraction. In healthy individuals,
VMSCs are mostly found to be in their contractile state but pro-inammatory stimuli and vascular injury can direct the cells into their synthetic, non-contractile phenotype [66, 67].
The mechanism by which VSMCs develop tension and contract is called actomyosin cross-bridge cycling. Increases in intracellular calcium concentrations by
Ca2+ entry from the extra-cellular uid triggers calcium calmodulin-dependent contraction of the smooth muscle cells. Ca2+ binds calmodulin to form a complex which
activates MLCK.The involvement of two enzymes, i.e. Ca2+ /calmodulin-dependent
MLCK and myosin light chain phosphatase (MLCP) both regulate the extend of
contraction. Activated MLCK is responsible for the phosphorylation of the two
RLCs which, together with two essential light chains, make up the thick laments
of the contractile unit. RLCs are wrapped around each α-helical neck region of the
myosin heavy chains (MHC). In the unphosphorylated state, binding of the myosin
motor heads to actin is prevented by intramolecular interactions of the RLCs and the
myosin motor heads. Phosphorylation of RLCs displaces the two myosin motor
heads and therefore enables cyclic binding to the actin laments with a consequential cell contraction and force development. A reduction of this force is obtained by
a decrease of intracellular Ca2+ levels, returning MLCK to an inactive state and a
MLCP dependent dephosphorylation of the RLCs [68].
Thin laments of the VSMC contractile unit consist of polymerized α-smooth
muscle actin (α-SMA), a SMC specic isoform encoded by ACTA2. Altogether they
can make up to 40% of the total cellular protein in SMCs. Mutations in ACTA2 are
found to disrupt amino acids in all four actin subdomains, which are predicted to
produce structurally-altered, unstable actin laments, an increase in monomeric
actin pool and a slower sliding of the myosin across mutant actin laments.
Therefore, the mutant actin will decrease the contractile ability of SMCs in response
to pulse pressures [54, 55].
Thick laments are part of the second major component of the VSMC contractile
unit, consisting of a SMC-specic isoform of MHC dimers encoded by MYH11.
Disease-causing MYH11 mutations are predicted to disrupt accurate polymerization
of myosin into thick laments. The duplication of MYH11 gene has also been shown
to increase autophagy and VSMC degradation, endoplasmic reticulum stress and
MHC expression. Additional disease modiers, either genetic or environmental, can
be an explanation why only a subset of the MYH11 duplication carriers cause
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heritable aortic disease. However, the exact mechanisms for this are currently still
unclear [68].
Mutations in amino acids 923–1914 that lead to haploinsufciency of MLCK,
diminish the contractile reserve of VSMCs, relative to the RLC phosphorylation
signaling. A bigger intracellular Ca2+ inux is needed to obtain the same fraction of
functionally active MLCK and thus contractile force. Therefore, a modest Ca2+
inux leads to reduced aortic VSMC contraction [68, 69].
Relaxation of VSMCs on the other hand, is obtained by a decrease in RLC
dephosphorylation which is controlled by type I cGMP-dependent protein kinase
(PRKG-1). Both PKG-1α and PKG-1β are encoded by PRKG1, however, the
PKG-1α splice variant is the major isoform present in aortic VSMCs. Nitric oxide
stimulates soluble guanylyl cyclase with subsequent increase in cellular cGMP levels. Upon binding with cGMP the catalytic domain of PKG-1α is released and activated, leading to the activation of the regulatory myosin binding subunit of the
phosphatase responsible for the dephosphorylation of the RLCs.
Mutations in MAT2A (which encodes methionine adenosyltransferase IIα
(MAT2α) that catalyze the synthesis of S-adenosylmethionine (SAM)) [25], are predicted to decrease the amount of SAM produced and lead to aortic disease. Multiple
hypotheses have been described to explain this clinical phenotype in affected individuals. One hypothesis is that the cause of the phenotype is reduction of DNA,
RNA and protein methylation in VSMCs, as SAM serves as a methyl donor in methylation reactions. Hypomethylation in SMCs occurs with phenotypic modulation
and proliferation and is associated with altered regulation of SMC differentiation
thereby increasing the predisposition to aortic wall weakness. Another hypothesis is
that decreased SAM levels can increase oxidative stress in VSMCs by reducing
glutathione activity, which increases VSMC sensitivity to angiotensin II (AngII)
leading to increased AngII signaling and to aortic aneurysms and dissections. A
third hypothesis is a loss of intracellular cysteine pools due to limited demethylated
SAM conversion into homocysteine. As a consequence, the cysteine-rich brillin-1
deposition into the ECM is greatly reduced with consequential weakening of aortic
wall as seen in MFS patients [59].
FOXE3 deciency caused by C-terminal mutations limits neural crest-derived
VSMC proliferation, survival and differentiation during development of the ascending aorta and arch. In physiological circumstances, increased biomechanical forces
on VSMCs of the ascending aorta induce FOXE3 expression, stimulating anti-apop-
totic pathways. Pathologically-decreased FoxE3 levels increase VSMC apoptosis,
which is seen in medial degeneration [
28].
M. H. A. M. Perik et al.
13.6.3 TGF-β Signalling Pathway
An important secreted polypeptide with widespread contributions to vascular development is transforming growth factor-beta (TGF-β), which is essential in cell development, growth, differentiation, migration, apoptosis and production of ECM.Three
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