62
exposed to shear stress, there are reorganization and upregulation of nuclear laminas which protect the DNA and the nucleus interior from the effects of shear stress
[30, 90]. Since lamins are involved in several nuclear functions including regulation
of gene expression, it is likely that alterations in the nuclear lamina response to
shear stress impacts gene expression. It is also hypothesized that a cellular phenotype, activated in response to well-defined laminar shear stress, resists the development of arteriosclerotic lesions, by activating protective signaling pathways. In
HGPS there is an abnormal nuclear lamina that leads to a more stiffened nucleus
and failure to respond normally to shear stress [30]. Therefore, progerin-expressing
cells, which do not respond normally to shear stress, contribute to the early development of arteriosclerosis in HGPS patients, evident by the fact that arteriosclerotic
plaques develop preferentially in regions of elevated shear flow [90]. Moreover, it
has been shown that HGPS neighboring, but unaffected cells, also have an altered
response to shear stress, further contributing to the severity of the vasculopathy of
HGPS [90].
Loss of SMCs in regions exposed to high fluidic shear stress, such as the aortic
and carotid arteries, is strong evidence that their normal adaptation to shear stress
is altered in HGPS. These altered responses are linked to changes in mechanotransduction pathways [111]. Progerin-expressing SMCs, exposed to high in vivo
hemodynamic forces, have a significant reduction in the expression of mechanotransduction-related proteins such as vinculin and vimentin.
In contrast to SMCs, progerin-expressing ECs seem to be more resistant to shear
stress than ECs without progerin. Indeed, an intact monolayer of vimentin-positive
ECs is typically observed in progeria mouse models [111]. In aortic regions presenting SMCs loss, ECs show more than an eightfold level of vimentin expression, in
comparison with ECs overlying adjacent aortic regions not depleted of SMCs. This
upregulation in vimentin helps ECs withstand the same mechanical forces that are
degenerative to SMCs. Furthermore, vimentin filaments in ECs associate with integrins to form cell-matrix adhesions through flow-induced focal contacts [111].
3.5 In Vitro Systems to Study Vascular Aging
Animal models are important tools to study aging, since they share common molecular mechanisms of pathophysiology with aged people, providing insight into the
molecular mechanisms of aging. Therefore, a wide range of in vivo vascular aging
models have been developed, such as mouse models of accelerated aging [10, 58,
72, 87, 137]. Nevertheless, vascular aging is a complex biological phenomenon in
which several components are involved. Thus, it is very unlikely that an individual
gene mutation in mice would recapitulate all the features of human aging.
Furthermore, it is difficult to identify cellular and molecular key players to disease
in whole-animal models. These limitations of vascular aging animal models lead to
the development of new in vitro vascular aging models.
P. R. Pitrez et al.
exposed to shear stress, there are reorganization and upregulation of nuclear laminas which protect the DNA and the nucleus interior from the effects of shear stress
[30, 90]. Since lamins are involved in several nuclear functions including regulation
of gene expression, it is likely that alterations in the nuclear lamina response to
shear stress impacts gene expression. It is also hypothesized that a cellular phenotype, activated in response to well-defined laminar shear stress, resists the development of arteriosclerotic lesions, by activating protective signaling pathways. In
HGPS there is an abnormal nuclear lamina that leads to a more stiffened nucleus
and failure to respond normally to shear stress [30]. Therefore, progerin-expressing
cells, which do not respond normally to shear stress, contribute to the early development of arteriosclerosis in HGPS patients, evident by the fact that arteriosclerotic
plaques develop preferentially in regions of elevated shear flow [90]. Moreover, it
has been shown that HGPS neighboring, but unaffected cells, also have an altered
response to shear stress, further contributing to the severity of the vasculopathy of
HGPS [90].
Loss of SMCs in regions exposed to high fluidic shear stress, such as the aortic
and carotid arteries, is strong evidence that their normal adaptation to shear stress
is altered in HGPS. These altered responses are linked to changes in mechanotransduction pathways [111]. Progerin-expressing SMCs, exposed to high in vivo
hemodynamic forces, have a significant reduction in the expression of mechanotransduction-related proteins such as vinculin and vimentin.
In contrast to SMCs, progerin-expressing ECs seem to be more resistant to shear
stress than ECs without progerin. Indeed, an intact monolayer of vimentin-positive
ECs is typically observed in progeria mouse models [111]. In aortic regions presenting SMCs loss, ECs show more than an eightfold level of vimentin expression, in
comparison with ECs overlying adjacent aortic regions not depleted of SMCs. This
upregulation in vimentin helps ECs withstand the same mechanical forces that are
degenerative to SMCs. Furthermore, vimentin filaments in ECs associate with integrins to form cell-matrix adhesions through flow-induced focal contacts [111].
3.5 In Vitro Systems to Study Vascular Aging
Animal models are important tools to study aging, since they share common molecular mechanisms of pathophysiology with aged people, providing insight into the
molecular mechanisms of aging. Therefore, a wide range of in vivo vascular aging
models have been developed, such as mouse models of accelerated aging [10, 58,
72, 87, 137]. Nevertheless, vascular aging is a complex biological phenomenon in
which several components are involved. Thus, it is very unlikely that an individual
gene mutation in mice would recapitulate all the features of human aging.
Furthermore, it is difficult to identify cellular and molecular key players to disease
in whole-animal models. These limitations of vascular aging animal models lead to
the development of new in vitro vascular aging models.
P. R. Pitrez et al.