55
signaling, is associated with increased oxidative stress, inflammation, fibrosis, and
DNA damage [91]. Altogether, changes in the expression of MMPs with aging contribute to the increased fibrosis and stiffening of the vessels.
Vascular calcification is a marker of vascular aging. It typically occurs after
deposition of calcium phosphate in distinct layers of the arteries. This is an active
process, similar to bone formation, which involves the differentiation of SMCs into
“osteoblast-like” cells that present a secretory phenotype [66]. SMCs synthesize
proteins such as alkaline phosphatase, osteopontin, osteocalcin, and collagen.
Inflammation and activation of the NF-κB pathway play the main role in triggering
SMCs into the osteogenic phenotype, by increasing levels of IL-6, tumor necrosis
factor-alpha (TNF-α), MMP-2, MMP-9, and cathepsin S [15, 21]. The fragmentation of elastin, described above, also contributes to SMCs differentiation and the
deposition of calcium [33]. The age-associated cell senescence of SMCs and their
secretory phenotype, associated with activation of the NF-κB process, contribute to
the differentiation of SMCs into the osteogenic phenotype [82]. Calcification in the
intima, present in atherosclerosis, reduces the lumen vessel diameter and causes
arterial dysfunction. In the media, calcification is concentric, with diffuse mineral
deposits and promotes an increase in the arterial stiffness [66].
3.3.2 Enhanced Fibrosis
Fibrosis is defined as the formation of excessive fibrous tissue, due to increased
deposition of ECM components [135]. It is an adaptive response that gradually
extends to the surrounding spaces and leads to increased arterial stiffening. Agingassociated factors, such as reduced nitric oxide (NO) availability, oxidative stress,
calcification, ECM remodeling, and a pro-inflammatory environment, all contribute
to increased fibrosis. Pro-hypertensive factors, such as angiotensin II (Ang II),
endothelin-1 (ET-1), and aldosterone, induce the activation of the signaling pathways p38 MAPK and TGF-β/SMAD, further promoting synthesis of fibrotic tissue
[51, 134]. Another factor that induces fibrosis is transglutaminase (TG2), a protein
that interacts with the ECM, which regulates fibroblast activity and ECM organization. The deregulation of the activity of TG2 leads to increased stiffness of the vessels [89]. Higher levels of MMP-2 and MMP-9 also contribute to the release of
TGF-β1, resulting in higher ECM deposition [130].
3.3.3 Vascular Cell Dysfunction
Impairment in EC vasodilatation capacity is one of the first signs of vessel aging
[106]. The main agents responsible for vasodilatation are endothelium-derived hyperpolarizing factor (EDHF), prostacyclin1 and NO [35]. EDHF contributes to endothelial vasodilatation and declines with age [26]. Prostacyclin is a cyclooxygenase
3 Physiological and Pathological Vascular Aging
signaling, is associated with increased oxidative stress, inflammation, fibrosis, and
DNA damage [91]. Altogether, changes in the expression of MMPs with aging contribute to the increased fibrosis and stiffening of the vessels.
Vascular calcification is a marker of vascular aging. It typically occurs after
deposition of calcium phosphate in distinct layers of the arteries. This is an active
process, similar to bone formation, which involves the differentiation of SMCs into
“osteoblast-like” cells that present a secretory phenotype [66]. SMCs synthesize
proteins such as alkaline phosphatase, osteopontin, osteocalcin, and collagen.
Inflammation and activation of the NF-κB pathway play the main role in triggering
SMCs into the osteogenic phenotype, by increasing levels of IL-6, tumor necrosis
factor-alpha (TNF-α), MMP-2, MMP-9, and cathepsin S [15, 21]. The fragmentation of elastin, described above, also contributes to SMCs differentiation and the
deposition of calcium [33]. The age-associated cell senescence of SMCs and their
secretory phenotype, associated with activation of the NF-κB process, contribute to
the differentiation of SMCs into the osteogenic phenotype [82]. Calcification in the
intima, present in atherosclerosis, reduces the lumen vessel diameter and causes
arterial dysfunction. In the media, calcification is concentric, with diffuse mineral
deposits and promotes an increase in the arterial stiffness [66].
3.3.2 Enhanced Fibrosis
Fibrosis is defined as the formation of excessive fibrous tissue, due to increased
deposition of ECM components [135]. It is an adaptive response that gradually
extends to the surrounding spaces and leads to increased arterial stiffening. Agingassociated factors, such as reduced nitric oxide (NO) availability, oxidative stress,
calcification, ECM remodeling, and a pro-inflammatory environment, all contribute
to increased fibrosis. Pro-hypertensive factors, such as angiotensin II (Ang II),
endothelin-1 (ET-1), and aldosterone, induce the activation of the signaling pathways p38 MAPK and TGF-β/SMAD, further promoting synthesis of fibrotic tissue
[51, 134]. Another factor that induces fibrosis is transglutaminase (TG2), a protein
that interacts with the ECM, which regulates fibroblast activity and ECM organization. The deregulation of the activity of TG2 leads to increased stiffness of the vessels [89]. Higher levels of MMP-2 and MMP-9 also contribute to the release of
TGF-β1, resulting in higher ECM deposition [130].
3.3.3 Vascular Cell Dysfunction
Impairment in EC vasodilatation capacity is one of the first signs of vessel aging
[106]. The main agents responsible for vasodilatation are endothelium-derived hyperpolarizing factor (EDHF), prostacyclin1 and NO [35]. EDHF contributes to endothelial vasodilatation and declines with age [26]. Prostacyclin is a cyclooxygenase
3 Physiological and Pathological Vascular Aging