61
arteriosclerotic plaques of HGPS large vessels, contributing to the development of
early arteriosclerosis [86]. The accumulation of both prelamin A and progerin at the
nuclear envelope results in increased NF- K B activation and systemic inflammation,
revealing a possibility that this pathway plays a critical role in premature vascular
aging [81]. It is also possible, though not yet studied, that HGPS-ECs also have an
impaired NO synthesis function. Overall, EC dysfunction reduces EC contribution
to arterioprotection and vascular repair.
Progressive loss of SMCs is a characteristic of HGPS patients, as well as in progeria mouse models [47]. SMCs depletion occurs mainly in arteries exposed to high
flow shear stress such as the aorta and carotid [126, 138]. The loss of SMCs occurs
in the media of the artery, with accumulation of matrix proteoglycan [23, 126]. The
SMCs remaining in the vessels of HGPS show marked premature senescence and,
it is thought, that SMC dysfunction is a major trigger of vascular calcification,
another hallmark of both physiological and accelerated aging. Progerin and prelamin A accumulation in the nucleus of SMCs leads to nuclear lamina dysfunction,
including impaired DNA damage response and repair. This in turn leads to the activation of senescence pathways in prelamin A-expressing SMCs, with induction of
senescence-associated secretory phenotype (SASP). SASP includes inflammatory
factors, extracellular matrix remodeling proteases, and proteins implicated in the
regulation of SMCs calcification, such as BMP2, Runx2, osteocalcin, osteopontin,
and osteoprotegerin [64]. Moreover, exposure of SMCs to calcifying medium leads
to upregulation of lamin A and prelamin A expression, accompanied by an increase
of pro-calcification factors and increased calcium deposition [47]. Besides the transition of SMCs to an “osteoblastic-like” phenotype, there are other factors that contribute to vascular calcification. There is enhanced formation of calcium phosphate
deposits in blood vessels likely due to mitochondrial dysfunction and ATP production. Progerin-expressing SMCs showed impaired mitochondrial dysfunction and
ATP production, leading to reduced synthesis of pyrophosphate (PPi), a potent
inhibitor of the formation of calcium deposits. Progerin-expressing SMCs also
showed upregulation of several enzymes responsible for PPi hydrolysis and of
phosphate synthesis [128].
Although not yet explored, it is possible that the remodeled ECM, which involves
the HGPS SMCs, has a large role in the development of vascular calcification. It has
already been shown that metalloproteinases are upregulated in human arteriosclerotic
plaques and that by inhibiting their activity, it is possible to reduce arterial calcification [94]. These evidences demonstrate the importance of the altered ECM in the
vasculopathy of physiological and accelerated aging.
3.4.4 Altered Response of Vascular Cells to Flow Shear Stress
Cells of the cardiovascular system are exposed to various types of hemodynamic
stress. Nucleus shape has been associated with adaptation to shear stress, an alteration that minimizes the total force exerted on the nuclei. Normally, when a cell is
3 Physiological and Pathological Vascular Aging
arteriosclerotic plaques of HGPS large vessels, contributing to the development of
early arteriosclerosis [86]. The accumulation of both prelamin A and progerin at the
nuclear envelope results in increased NF- K B activation and systemic inflammation,
revealing a possibility that this pathway plays a critical role in premature vascular
aging [81]. It is also possible, though not yet studied, that HGPS-ECs also have an
impaired NO synthesis function. Overall, EC dysfunction reduces EC contribution
to arterioprotection and vascular repair.
Progressive loss of SMCs is a characteristic of HGPS patients, as well as in progeria mouse models [47]. SMCs depletion occurs mainly in arteries exposed to high
flow shear stress such as the aorta and carotid [126, 138]. The loss of SMCs occurs
in the media of the artery, with accumulation of matrix proteoglycan [23, 126]. The
SMCs remaining in the vessels of HGPS show marked premature senescence and,
it is thought, that SMC dysfunction is a major trigger of vascular calcification,
another hallmark of both physiological and accelerated aging. Progerin and prelamin A accumulation in the nucleus of SMCs leads to nuclear lamina dysfunction,
including impaired DNA damage response and repair. This in turn leads to the activation of senescence pathways in prelamin A-expressing SMCs, with induction of
senescence-associated secretory phenotype (SASP). SASP includes inflammatory
factors, extracellular matrix remodeling proteases, and proteins implicated in the
regulation of SMCs calcification, such as BMP2, Runx2, osteocalcin, osteopontin,
and osteoprotegerin [64]. Moreover, exposure of SMCs to calcifying medium leads
to upregulation of lamin A and prelamin A expression, accompanied by an increase
of pro-calcification factors and increased calcium deposition [47]. Besides the transition of SMCs to an “osteoblastic-like” phenotype, there are other factors that contribute to vascular calcification. There is enhanced formation of calcium phosphate
deposits in blood vessels likely due to mitochondrial dysfunction and ATP production. Progerin-expressing SMCs showed impaired mitochondrial dysfunction and
ATP production, leading to reduced synthesis of pyrophosphate (PPi), a potent
inhibitor of the formation of calcium deposits. Progerin-expressing SMCs also
showed upregulation of several enzymes responsible for PPi hydrolysis and of
phosphate synthesis [128].
Although not yet explored, it is possible that the remodeled ECM, which involves
the HGPS SMCs, has a large role in the development of vascular calcification. It has
already been shown that metalloproteinases are upregulated in human arteriosclerotic
plaques and that by inhibiting their activity, it is possible to reduce arterial calcification [94]. These evidences demonstrate the importance of the altered ECM in the
vasculopathy of physiological and accelerated aging.
3.4.4 Altered Response of Vascular Cells to Flow Shear Stress
Cells of the cardiovascular system are exposed to various types of hemodynamic
stress. Nucleus shape has been associated with adaptation to shear stress, an alteration that minimizes the total force exerted on the nuclei. Normally, when a cell is
3 Physiological and Pathological Vascular Aging