57
characterized by the shortening of telomere size and loss of the proliferative capacity of ECs [80]. Stress-induced premature senescence occurs after cell exposure to
stressful conditions such as altered glucose levels, oxidized low-density lipoprotein,
homocysteine, ceramide, Ang II, elevated blood pressure, increased ROS levels, and
inflammation [115]. Senescent ECs display alterations in gene transcription and
protein profile expression. Levels of transcription of IL-1α, IL-8, fibronectin,
ICAM-1, p1, p53, and iNOS are shown to be upregulated, while eNOS is downregulated. Protein degradation of endothelial differentiation-related factor-1 (EDRF-1)
and cyclin-dependent kinase 2 (CDK2) are increased in senescent ECs [49, 73, 80].
3.3.4 Altered Response of Vascular Cells to Flow Shear Stress
Blood flow in vessels creates a parallel friction force in the endothelium, called fluid
shear stress, which influences the phenotype of ECs. ECs sense the shear stress and
dynamically respond, by converting mechanical forces into intracellular signals [8].
This process is carried out by mechanotransducers such as glycocalyx, ion channels, G proteins, adhesion molecules, and the cytoskeleton [8]. The prolonged exposition to blood flow causes structural changes, including elongation of ECs in the
direction of the blood flow, and the orientation of the actin cytoskeleton, microtubules, and intermediate filaments in the flow direction [62]. During aging, there is
an altered response of ECs to shear stress, which can contribute to the development
of atherosclerotic plaques [24]. As mentioned above, one of the main contributors
for endothelial dysfunction is the reduction of NO availability due to the reduced
activity of eNOS. Activation of eNOS can be carried out by fluid shear stress created
by the blood flow in the endothelial layer [69]. In aged vessels, the reduced availability of NO can be associated with the lack of response of ECs to the shear stress
and consequent decrease in NO production. The inflammatory process is also influenced by shear stress. During aging low levels of shear stress can promote arterial
inflammation, through the induction of NK-κB expression in ECs and can contribute to the formation of atherosclerotic plaques [29]. An altered response of SMCs to
shear stress also occurs in aged cells. In this case, increased aortic intraluminal
pressure causes activation of ERK1/2, p38 MAPK, and JNK proteins [98].
3.4 Pathological Vascular Aging: The Example
of Hutchinson-Gilford Progeria Syndrome (HGPS)
HGPS is a rare disease in which patients exhibit accelerated aging-related symptoms such as alopecia, osteoporosis, subcutaneous fat loss, lipodystrophy, and skin
wrinkling [67]. Cardiovascular complications are the most devastating symptoms of
this syndrome. Children develop progressive arteriosclerosis of the coronary and
3 Physiological and Pathological Vascular Aging
characterized by the shortening of telomere size and loss of the proliferative capacity of ECs [80]. Stress-induced premature senescence occurs after cell exposure to
stressful conditions such as altered glucose levels, oxidized low-density lipoprotein,
homocysteine, ceramide, Ang II, elevated blood pressure, increased ROS levels, and
inflammation [115]. Senescent ECs display alterations in gene transcription and
protein profile expression. Levels of transcription of IL-1α, IL-8, fibronectin,
ICAM-1, p1, p53, and iNOS are shown to be upregulated, while eNOS is downregulated. Protein degradation of endothelial differentiation-related factor-1 (EDRF-1)
and cyclin-dependent kinase 2 (CDK2) are increased in senescent ECs [49, 73, 80].
3.3.4 Altered Response of Vascular Cells to Flow Shear Stress
Blood flow in vessels creates a parallel friction force in the endothelium, called fluid
shear stress, which influences the phenotype of ECs. ECs sense the shear stress and
dynamically respond, by converting mechanical forces into intracellular signals [8].
This process is carried out by mechanotransducers such as glycocalyx, ion channels, G proteins, adhesion molecules, and the cytoskeleton [8]. The prolonged exposition to blood flow causes structural changes, including elongation of ECs in the
direction of the blood flow, and the orientation of the actin cytoskeleton, microtubules, and intermediate filaments in the flow direction [62]. During aging, there is
an altered response of ECs to shear stress, which can contribute to the development
of atherosclerotic plaques [24]. As mentioned above, one of the main contributors
for endothelial dysfunction is the reduction of NO availability due to the reduced
activity of eNOS. Activation of eNOS can be carried out by fluid shear stress created
by the blood flow in the endothelial layer [69]. In aged vessels, the reduced availability of NO can be associated with the lack of response of ECs to the shear stress
and consequent decrease in NO production. The inflammatory process is also influenced by shear stress. During aging low levels of shear stress can promote arterial
inflammation, through the induction of NK-κB expression in ECs and can contribute to the formation of atherosclerotic plaques [29]. An altered response of SMCs to
shear stress also occurs in aged cells. In this case, increased aortic intraluminal
pressure causes activation of ERK1/2, p38 MAPK, and JNK proteins [98].
3.4 Pathological Vascular Aging: The Example
of Hutchinson-Gilford Progeria Syndrome (HGPS)
HGPS is a rare disease in which patients exhibit accelerated aging-related symptoms such as alopecia, osteoporosis, subcutaneous fat loss, lipodystrophy, and skin
wrinkling [67]. Cardiovascular complications are the most devastating symptoms of
this syndrome. Children develop progressive arteriosclerosis of the coronary and
3 Physiological and Pathological Vascular Aging