53
factor, are related with atherogenesis and consequently with vascular aging [119].
Lymphocyte telomere length, easily accessed through peripheral blood, may be
used as a biomarker of vessel aging since it is related with stem cell and endothelial
progenitor cells (EPCs) telomere length [34]. Inflammatory markers such as the
nuclear factor-kappa B (NF- K B) and insulin growth factor-1 (IGF-1) maybe also be
used as biomarkers of vascular aging. Other biomarkers are strictly linked with
senescence and can reflect cell cycle arrest (e.g., p53, p21, p16
INK4a
), absence of cellular proliferation (e.g., lack of BrdU incorporation, Ki67), activation of doublestranded brakes (e.g., H2AX, p53BP1 foci), expression of inflammatory factors
(e.g., interleukin-6 and interleukin-8), cell senescence (SA-β-gal), loss of lamin B1,
and activation of pathways that regulate the secretory phenotype (e.g., p-p65 or
p-p38) [20, 32, 40, 95].
3.3 Physiological Vascular Aging
Vascular aging is characterized by biophysical changes. There is a fatigue of the
vessels resulting from sustained mechanical stress-associated pressure caused by
blood flow. The extracellular matrix (ECM) becomes stiffer, losing elasticity and,
therefore, the ability to stretch [79]. In addition, endothelial cells (ECs) become
dysfunctional as result of a pro-inflammatory environment and increased oxidative
stress [116].
3.3.1 Altered ECM Remodeling
The vessel wall is mainly composed of an ECM which provides structural support
and defines the vessel’s mechanical properties. By interacting with vascular cells,
the ECM is able to act as a signal transductor to modulate cell proliferation, survival, differentiation, and gene expression. The major components of the vascular
ECM are collagen and elastin, complemented by other molecules including fibronectin, microfibrils, proteoglycans, and glycoproteins [136]. Different sections of
the blood vessel wall have different compositions of ECM proteins [129]. In the
tunica intima, ECs lined the vessel luminal surface, attaching to a basement membrane containing mainly laminin, type IV collagen, nitrogen, perlecan, types XV
and VIII collagens, and fibronectin [9, 136]. Between the intima and the tunica
media, arteries and veins are supported by the internal elastic lamina [31, 129]. In
the tunica media, vascular smooth muscle cells (SMCs) and elastins are the major
components. Elastin forms concentric fenestrated sheets, intercalated with collagen
fibers and proteoglycans, which connects with SMCs [85]. Elastin is an elastic fiber
produced by SMCs, presenting low tensile strength that contributes to the elasticity
of the vessels and to store the recoiling energy, contributing to vessel compliancy
[136]. The percentage of lamellar units present in the vessel varies with the tensile
3 Physiological and Pathological Vascular Aging
factor, are related with atherogenesis and consequently with vascular aging [119].
Lymphocyte telomere length, easily accessed through peripheral blood, may be
used as a biomarker of vessel aging since it is related with stem cell and endothelial
progenitor cells (EPCs) telomere length [34]. Inflammatory markers such as the
nuclear factor-kappa B (NF- K B) and insulin growth factor-1 (IGF-1) maybe also be
used as biomarkers of vascular aging. Other biomarkers are strictly linked with
senescence and can reflect cell cycle arrest (e.g., p53, p21, p16
INK4a
), absence of cellular proliferation (e.g., lack of BrdU incorporation, Ki67), activation of doublestranded brakes (e.g., H2AX, p53BP1 foci), expression of inflammatory factors
(e.g., interleukin-6 and interleukin-8), cell senescence (SA-β-gal), loss of lamin B1,
and activation of pathways that regulate the secretory phenotype (e.g., p-p65 or
p-p38) [20, 32, 40, 95].
3.3 Physiological Vascular Aging
Vascular aging is characterized by biophysical changes. There is a fatigue of the
vessels resulting from sustained mechanical stress-associated pressure caused by
blood flow. The extracellular matrix (ECM) becomes stiffer, losing elasticity and,
therefore, the ability to stretch [79]. In addition, endothelial cells (ECs) become
dysfunctional as result of a pro-inflammatory environment and increased oxidative
stress [116].
3.3.1 Altered ECM Remodeling
The vessel wall is mainly composed of an ECM which provides structural support
and defines the vessel’s mechanical properties. By interacting with vascular cells,
the ECM is able to act as a signal transductor to modulate cell proliferation, survival, differentiation, and gene expression. The major components of the vascular
ECM are collagen and elastin, complemented by other molecules including fibronectin, microfibrils, proteoglycans, and glycoproteins [136]. Different sections of
the blood vessel wall have different compositions of ECM proteins [129]. In the
tunica intima, ECs lined the vessel luminal surface, attaching to a basement membrane containing mainly laminin, type IV collagen, nitrogen, perlecan, types XV
and VIII collagens, and fibronectin [9, 136]. Between the intima and the tunica
media, arteries and veins are supported by the internal elastic lamina [31, 129]. In
the tunica media, vascular smooth muscle cells (SMCs) and elastins are the major
components. Elastin forms concentric fenestrated sheets, intercalated with collagen
fibers and proteoglycans, which connects with SMCs [85]. Elastin is an elastic fiber
produced by SMCs, presenting low tensile strength that contributes to the elasticity
of the vessels and to store the recoiling energy, contributing to vessel compliancy
[136]. The percentage of lamellar units present in the vessel varies with the tensile
3 Physiological and Pathological Vascular Aging