54
strength that the vessel is subjected to, being higher in the larger and more proximal
vessels that withstand higher wall tension [11]. Finally, tunica adventitia, the outside layer of the vessels, is rich in collagen type I and III. Collagen provides high
tensile strength, which prevents wall rupture due to blood pressure. The production
of the adventitia proteins is mainly done by fibroblasts [19, 136].
In aged blood vessels, the endothelium, the SMCs, and the ECM suffer structural
and functional changes that lead to arterial stiffness, fibrosis, and endothelial dysfunction [88]. The ECM in the vascular wall becomes thicker and stiffer with aging,
due to several factors including (1) increase of the collagen to elastin ratio, (2)
impairment of the balance between ECM degradation and production, and (3) dysfunction of newly synthesized ECM [54]. Collagens and elastin are the major components of the blood vessel’s ECM and the absolute and relative quantities of these
proteins define the biomechanical properties of the vessels [100]. Collagen provides
the tensile strength while elastin the elastic properties for the vessels [117]. Elastin
represents approximately 50% of the arterial wall dry weight, and it is mainly produced by SMCs and fibroblasts, which have a low turnover rate during their life [18].
As mentioned above, through aging, changes in the composition and structure of
collagen, as well as the ratio between elastin to collagen, contribute to a decrease in
the total arterial compliance [118]. An increase in the content of collagen types I and
III across the vessel wall [57] occurs during aging, namely, in the adventitia, causing the stiffening of the vessels [39]. In addition, increased cross-linking between
collagen fibers leads to more insoluble fibers and, thus, less availability for enzymatic degradation, with an increased tensile strength [41]. The cross-linking process may be driven by enzymes, such as lysyl oxidases, which promote the formation
of inter- and intramolecular cross-links [96] or by the accumulation of advanced
glycation end products (AGEs) [43]. AGEs are formed by non-enzymatic glycation
of proteins and lipids and their production is accelerated with aging. Collagen and
elastin, present in the vessels, have a low turnover rate and become more susceptible
to glycation [78, 104]. With aging, the elastin content of blood vessels decreases,
thereby increasing the collagen to elastin ratio [117]. Moreover, elastin suffers
structural changes, due to the repeated mechanical forces during stretches and relaxation in the cardiac cycle, as well as increased oxidative stress that concomitantly
contributes to fragmentation and rupture of elastin fibers [33]. Elastin cross-linking
with AGEs also contributes to an increase in fragility and fragmentation of this protein [107].
Another feature, which contributes to ECM remodeling with aging, is the imbalance between the synthesis and degradation of ECM components. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading ECM components
[14]. With age, an increase in the activity of MMP-2/MMP-7/MMP-9/MMP-14 in
the aortic walls of rodents, nonhuman primates, and humans has been reported
[132]. Increases in MMP-2 activity in the aorta are associated with elastin fragmentation [77]. Furthermore, MMP-2 expression leads to the stimulation of transforming growth factor (TGF-β1) signaling; increased production of collagens I, II, and
III by vascular SMCs; and increased secretion of fibronectin [132]. Activation of
MMP-9, by pro-hypertensive factors, shear stress, pressure, and TGF-β1/SMAD
P. R. Pitrez et al.
strength that the vessel is subjected to, being higher in the larger and more proximal
vessels that withstand higher wall tension [11]. Finally, tunica adventitia, the outside layer of the vessels, is rich in collagen type I and III. Collagen provides high
tensile strength, which prevents wall rupture due to blood pressure. The production
of the adventitia proteins is mainly done by fibroblasts [19, 136].
In aged blood vessels, the endothelium, the SMCs, and the ECM suffer structural
and functional changes that lead to arterial stiffness, fibrosis, and endothelial dysfunction [88]. The ECM in the vascular wall becomes thicker and stiffer with aging,
due to several factors including (1) increase of the collagen to elastin ratio, (2)
impairment of the balance between ECM degradation and production, and (3) dysfunction of newly synthesized ECM [54]. Collagens and elastin are the major components of the blood vessel’s ECM and the absolute and relative quantities of these
proteins define the biomechanical properties of the vessels [100]. Collagen provides
the tensile strength while elastin the elastic properties for the vessels [117]. Elastin
represents approximately 50% of the arterial wall dry weight, and it is mainly produced by SMCs and fibroblasts, which have a low turnover rate during their life [18].
As mentioned above, through aging, changes in the composition and structure of
collagen, as well as the ratio between elastin to collagen, contribute to a decrease in
the total arterial compliance [118]. An increase in the content of collagen types I and
III across the vessel wall [57] occurs during aging, namely, in the adventitia, causing the stiffening of the vessels [39]. In addition, increased cross-linking between
collagen fibers leads to more insoluble fibers and, thus, less availability for enzymatic degradation, with an increased tensile strength [41]. The cross-linking process may be driven by enzymes, such as lysyl oxidases, which promote the formation
of inter- and intramolecular cross-links [96] or by the accumulation of advanced
glycation end products (AGEs) [43]. AGEs are formed by non-enzymatic glycation
of proteins and lipids and their production is accelerated with aging. Collagen and
elastin, present in the vessels, have a low turnover rate and become more susceptible
to glycation [78, 104]. With aging, the elastin content of blood vessels decreases,
thereby increasing the collagen to elastin ratio [117]. Moreover, elastin suffers
structural changes, due to the repeated mechanical forces during stretches and relaxation in the cardiac cycle, as well as increased oxidative stress that concomitantly
contributes to fragmentation and rupture of elastin fibers [33]. Elastin cross-linking
with AGEs also contributes to an increase in fragility and fragmentation of this protein [107].
Another feature, which contributes to ECM remodeling with aging, is the imbalance between the synthesis and degradation of ECM components. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading ECM components
[14]. With age, an increase in the activity of MMP-2/MMP-7/MMP-9/MMP-14 in
the aortic walls of rodents, nonhuman primates, and humans has been reported
[132]. Increases in MMP-2 activity in the aorta are associated with elastin fragmentation [77]. Furthermore, MMP-2 expression leads to the stimulation of transforming growth factor (TGF-β1) signaling; increased production of collagens I, II, and
III by vascular SMCs; and increased secretion of fibronectin [132]. Activation of
MMP-9, by pro-hypertensive factors, shear stress, pressure, and TGF-β1/SMAD
P. R. Pitrez et al.