60
expression of ECM components and decreased expression of ECM remodeling
enzymes, which leads to structural effects on tissue function and also lead to signaling imbalances.
Several pathways regulating ECM are affected in HGPS. Mutant lamin A is
accountable for the inhibition of the canonical Wnt signaling pathway, which is
implicated in the regulation of genes encoding ECM proteins [53]. TGF-β1/SMAD
pathway has also been implicated in HGPS. This pathway can be activated through
integrins, via mechanical force, contributing to increased collagen synthesis and,
therefore, fibrosis [2]. Expression of TGFβ1 increases in an age-dependent manner
in both HGPS and healthy cell lines. In postnatal tissues, especially those subjected
to extensive mechanical stress, such as the skeletal and cardiovascular systems, the
ECM assumes a structural role in maintaining tissue integrity and homeostasis [16].
In HGPS and physiological aging, there is a concomitant alteration of ECM components and pathways that regulate ECM synthesis and organization, leading to a
vicious cycle of matrix remodeling that contributes to the vasculopathy of aging.
3.4.2 Arterial Stiffening and Fibrosis
Progressive development of fibrotic arteriosclerosis, associated with an abnormal
ECM content, reveals a major role of the ECM in the vasculopathy of HGPS patients
[111, 138]. Similar to normal aged individuals, HGPS children show typically intimal fibrotic arteriosclerotic plaques in the main cardiac arteries. These lesions have
a complex morphology, including thinning of the medial layer of the vessels, subjacent to the thick arteriosclerotic plaque in the intimal region, a necrotic core, and
foci of chronic inflammation. HGPS patients show evidence of marked fibrosis of
the adventitial layer of large vessels, with a dense perimeter of collagen. In contrast,
the same adventitial changes are not observed in normal aged individuals [23, 138].
HGPS fibroblasts have increased levels of ROS and protein oxidation, as well as
decreased proteasome activity, thus contributing to cell dysfunction and altered production of ECM proteins [16]. Extensive calcification of the arteries is also frequently observed in HGPS (Fig. 3.1).
3.4.3 Vascular Cell Dysfunction
Arteriosclerosis progression and severity in HGPS vascular systems are correlated
with the accumulation of vascular senescent cells [16]. Senescent ECs in arteriosclerotic patients are characterized by low EC growth potential, as well as increased
DNA damage and oxidative stress [16]. Moreover, ECs with a HGPS phenotype
release inflammatory molecules and express higher levels of ICAM-1, after TNF-α
stimulation, than non-HGPS ECs [13]. The increase in ICAM-1 increases the adhesion of monocytes, described as the first event in the initiation of arteriosclerosis
[13]. This may explain the increased inflammation and macrophage localization in
P. R. Pitrez et al.
expression of ECM components and decreased expression of ECM remodeling
enzymes, which leads to structural effects on tissue function and also lead to signaling imbalances.
Several pathways regulating ECM are affected in HGPS. Mutant lamin A is
accountable for the inhibition of the canonical Wnt signaling pathway, which is
implicated in the regulation of genes encoding ECM proteins [53]. TGF-β1/SMAD
pathway has also been implicated in HGPS. This pathway can be activated through
integrins, via mechanical force, contributing to increased collagen synthesis and,
therefore, fibrosis [2]. Expression of TGFβ1 increases in an age-dependent manner
in both HGPS and healthy cell lines. In postnatal tissues, especially those subjected
to extensive mechanical stress, such as the skeletal and cardiovascular systems, the
ECM assumes a structural role in maintaining tissue integrity and homeostasis [16].
In HGPS and physiological aging, there is a concomitant alteration of ECM components and pathways that regulate ECM synthesis and organization, leading to a
vicious cycle of matrix remodeling that contributes to the vasculopathy of aging.
3.4.2 Arterial Stiffening and Fibrosis
Progressive development of fibrotic arteriosclerosis, associated with an abnormal
ECM content, reveals a major role of the ECM in the vasculopathy of HGPS patients
[111, 138]. Similar to normal aged individuals, HGPS children show typically intimal fibrotic arteriosclerotic plaques in the main cardiac arteries. These lesions have
a complex morphology, including thinning of the medial layer of the vessels, subjacent to the thick arteriosclerotic plaque in the intimal region, a necrotic core, and
foci of chronic inflammation. HGPS patients show evidence of marked fibrosis of
the adventitial layer of large vessels, with a dense perimeter of collagen. In contrast,
the same adventitial changes are not observed in normal aged individuals [23, 138].
HGPS fibroblasts have increased levels of ROS and protein oxidation, as well as
decreased proteasome activity, thus contributing to cell dysfunction and altered production of ECM proteins [16]. Extensive calcification of the arteries is also frequently observed in HGPS (Fig. 3.1).
3.4.3 Vascular Cell Dysfunction
Arteriosclerosis progression and severity in HGPS vascular systems are correlated
with the accumulation of vascular senescent cells [16]. Senescent ECs in arteriosclerotic patients are characterized by low EC growth potential, as well as increased
DNA damage and oxidative stress [16]. Moreover, ECs with a HGPS phenotype
release inflammatory molecules and express higher levels of ICAM-1, after TNF-α
stimulation, than non-HGPS ECs [13]. The increase in ICAM-1 increases the adhesion of monocytes, described as the first event in the initiation of arteriosclerosis
[13]. This may explain the increased inflammation and macrophage localization in
P. R. Pitrez et al.