56
(COX)-derived vasodilator, and its contribution to endothelial vasodilatation is lost
with age, in humans [105]. On the other hand, the contribution of COX- derived
contractile factors, such as thromboxane A 2 , increases with age [113, 125]. NO is
synthesized by endothelial nitric oxide synthase (eNOS), whose activity is decreased
with aging, leading to reduced availability of NO and decreased endothelial vasodilatation. This lowered availability of NO is also associated with increased reactive
oxygen species (ROS) production and consequent excessive oxidative stress, by
modulating the production of superoxide in human vessels [45]. Moreover, NO
reacts with superoxide to produce peroxynitrite, a highly reactive specie that is cytotoxic and contributes to vascular aging [123].
One hallmark of vascular aging is EC dysfunction, triggered by chronic oxidative stress [99]. An increase in oxidative stress on aged vessels has been observed
both in animal models and in humans [48, 120]. Part of this effect is mediated by
ROS. An imbalance in ROS production can lead to the accumulation of damaged or
misfolded proteins, DNA mutations, inflammation [122], and EC senescence [70].
The main sources of ROS that lead to oxidative stress in aged vessels are NADPH
oxidases, xanthine oxidase, uncoupled NO synthase, and the mitochondrial respiratory chain [35]. NADPH oxidases are involved in the generation of superoxide and
are upregulated in the presence of cardiovascular risk factors, including aging [17,
76]. Xanthine oxidase is an enzyme capable of producing ROS, and its accumulation in the aortic wall has been associated with aging [83]. The synthesis of NO by
nitric oxide synthase is done by catalyzing the conversion of L-arginine to
L-citrulline. For the reaction to occur, dimerization of the enzyme L-arginine and
the cofactor tetrahydrobiopterin (BH 4 ) have to be present. Uncoupling of NO synthase happens when L-arginine and BH 4 are not present. When this occurs, it has
been described that there is an increase in ROS production [112]. The mitochondria
are primarily responsible for ROS production, through the respiratory chain [124].
With age, there is an accumulation of impaired mitochondria that leads to oxidative
stress and contributes to vascular aging and impaired vasodilatation.
EC dysfunction triggered by inflammation is another hallmark of vascular aging
[99]. In aged individuals, there is an increase of pro-inflammatory factors such as
TNF-α, IL-1β, IL-6, CRP, Ang II, MMPs, calpain-1, monocyte chemoattractant
protein- 1 (MCP-1), interferon gamma (IFN-γ), and intercellular adhesion molecules (ICAM) [61, 131]. Upregulation of TNF-α has been described and associated
with oxidative stress, endothelial dysfunction, apoptosis, and impairment of endothelium dilatation. The pro-inflammatory cytokine IL-6 is also associated with vascular diseases in aging. The inflammatory response in vascular cells is mainly
mediated by the transcription factor NF-κB. When activated, it promotes the
transcription of pro-inflammatory cytokines that are shown to be highly active and
related with increased oxidative stress and endothelial dysfunction [1, 61].
Another hallmark of vascular aging is EC dysfunction triggered by senescence.
The loss of the replicative capacity of ECs impairs the response to injury and the
repair of dysfunctional endothelium [42]. The senescent phenotype in ECs can be
due to replicative senescence or stress-induced premature senescence [42].
Replicative senescence occurs due to the limited potential of cell division and is
P. R. Pitrez et al.
(COX)-derived vasodilator, and its contribution to endothelial vasodilatation is lost
with age, in humans [105]. On the other hand, the contribution of COX- derived
contractile factors, such as thromboxane A 2 , increases with age [113, 125]. NO is
synthesized by endothelial nitric oxide synthase (eNOS), whose activity is decreased
with aging, leading to reduced availability of NO and decreased endothelial vasodilatation. This lowered availability of NO is also associated with increased reactive
oxygen species (ROS) production and consequent excessive oxidative stress, by
modulating the production of superoxide in human vessels [45]. Moreover, NO
reacts with superoxide to produce peroxynitrite, a highly reactive specie that is cytotoxic and contributes to vascular aging [123].
One hallmark of vascular aging is EC dysfunction, triggered by chronic oxidative stress [99]. An increase in oxidative stress on aged vessels has been observed
both in animal models and in humans [48, 120]. Part of this effect is mediated by
ROS. An imbalance in ROS production can lead to the accumulation of damaged or
misfolded proteins, DNA mutations, inflammation [122], and EC senescence [70].
The main sources of ROS that lead to oxidative stress in aged vessels are NADPH
oxidases, xanthine oxidase, uncoupled NO synthase, and the mitochondrial respiratory chain [35]. NADPH oxidases are involved in the generation of superoxide and
are upregulated in the presence of cardiovascular risk factors, including aging [17,
76]. Xanthine oxidase is an enzyme capable of producing ROS, and its accumulation in the aortic wall has been associated with aging [83]. The synthesis of NO by
nitric oxide synthase is done by catalyzing the conversion of L-arginine to
L-citrulline. For the reaction to occur, dimerization of the enzyme L-arginine and
the cofactor tetrahydrobiopterin (BH 4 ) have to be present. Uncoupling of NO synthase happens when L-arginine and BH 4 are not present. When this occurs, it has
been described that there is an increase in ROS production [112]. The mitochondria
are primarily responsible for ROS production, through the respiratory chain [124].
With age, there is an accumulation of impaired mitochondria that leads to oxidative
stress and contributes to vascular aging and impaired vasodilatation.
EC dysfunction triggered by inflammation is another hallmark of vascular aging
[99]. In aged individuals, there is an increase of pro-inflammatory factors such as
TNF-α, IL-1β, IL-6, CRP, Ang II, MMPs, calpain-1, monocyte chemoattractant
protein- 1 (MCP-1), interferon gamma (IFN-γ), and intercellular adhesion molecules (ICAM) [61, 131]. Upregulation of TNF-α has been described and associated
with oxidative stress, endothelial dysfunction, apoptosis, and impairment of endothelium dilatation. The pro-inflammatory cytokine IL-6 is also associated with vascular diseases in aging. The inflammatory response in vascular cells is mainly
mediated by the transcription factor NF-κB. When activated, it promotes the
transcription of pro-inflammatory cytokines that are shown to be highly active and
related with increased oxidative stress and endothelial dysfunction [1, 61].
Another hallmark of vascular aging is EC dysfunction triggered by senescence.
The loss of the replicative capacity of ECs impairs the response to injury and the
repair of dysfunctional endothelium [42]. The senescent phenotype in ECs can be
due to replicative senescence or stress-induced premature senescence [42].
Replicative senescence occurs due to the limited potential of cell division and is
P. R. Pitrez et al.