Atherogenesis and ageing

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The culture of SMCs is a useful model system because under these conditions the cells show many of the functional changes characteristic of atherogenesis, in particular the ability to proliferate and to secrete collagen (Campbell & Campbell

FIG. 3. Relationship between hormone-induced migration and corresponding inhibition due to Ca2+ channel blockade by diltiazem in vascular smooth muscle cells from rat aorta and human femoral artery. The inhibition decreases directly proportionally to stimulation level either by IGF1 or insulin (bottom). Unpublished experiments performed in the Boyden chamber.

FIG. 3. Relationship between hormone-induced migration and corresponding inhibition due to Ca2+ channel blockade by diltiazem in vascular smooth muscle cells from rat aorta and human femoral artery. The inhibition decreases directly proportionally to stimulation level either by IGF1 or insulin (bottom). Unpublished experiments performed in the Boyden chamber.

1987, Massy & Keane 1996). The in vitro proliferating SMCs develop cytoskeletal features similar to those observed in fetal and pathological states (Skalli et al 1986). Essentially, SMCs exhibit two phenotypes in culture: one able to proliferate and the other to differentiate, recalling the in vivo fetal and contractile phenotypes, respectively. The terminal diferentiation in culture resembles the behaviour observed in other cells such as melanocytes (Medrano et al 1994). Proliferating SMCs in vivo assume fetal phenotypic features which are also observed in cultured cells (Desmouliere & Gabbiani 1992).

As the proliferation of human vascular SMCs characterizes the atherogenesis, it seems of interest to investigate the mitotic activity in cultured SMCs dependent on

FIG. 4. Inhibition of insulin stimulation of proliferation, migration and collagen secretion in human vascular smooth muscle cells (hvSMCs) due to receptor blocking antibodies, indicating the mechanism of action. The addition of IGF1 receptor blocking antibody inhibits the proliferative effect of insulin, whereas the opposite occurs in the case of migration. Similarly to proliferation, the insulin receptor blocking antibody does not show any effect on collagen secretion in spite of its inhibition of glucose uptake. White columns: incubations of hvSMCs with insulin and specific receptor blocking antibody (IRAb). Hatched columns: those with IGFl-receptor blocking antibody (IGFlRAb). *Dispersed cells from artery; the others from the culture (2-4 passage). ***P <0.0001; NS, not statistically significant (results partially published in Ruiz-Torres et al 1998, Munoz et al 1998).

FIG. 4. Inhibition of insulin stimulation of proliferation, migration and collagen secretion in human vascular smooth muscle cells (hvSMCs) due to receptor blocking antibodies, indicating the mechanism of action. The addition of IGF1 receptor blocking antibody inhibits the proliferative effect of insulin, whereas the opposite occurs in the case of migration. Similarly to proliferation, the insulin receptor blocking antibody does not show any effect on collagen secretion in spite of its inhibition of glucose uptake. White columns: incubations of hvSMCs with insulin and specific receptor blocking antibody (IRAb). Hatched columns: those with IGFl-receptor blocking antibody (IGFlRAb). *Dispersed cells from artery; the others from the culture (2-4 passage). ***P <0.0001; NS, not statistically significant (results partially published in Ruiz-Torres et al 1998, Munoz et al 1998).

the age of the donor. The proliferation rate of SMCs decreases in the culture as donor age advances (Ruiz-Torres et al 1999). The decline reaches the zero point that is the total loss of proliferative activity, at age over 100 years, near the limit of maximum life potential for human beings. Therefore age is a factor which decreases the ability of vascular SMCs to proliferate. The meaning is the same for in vivo as in vitro. Nevertheless, cultured cells age according the passage numbers as described by Hayflick (Smith & Hayflick 1974).

The cellular expression of ageing in vivo or in vitro is the progressive appearance of senescent cells, so that cells have a finite life potential (Hayflick 1987). Senescent cells lose their capacity to proliferate despite potentially remaining in the tissue or culture for a relatively long time (Matsumura et al 1979). A similar phenomenon occurs regarding migration capacity. We recently found that the basal migration of human vascular SMCs decreases as donor's age advances. The slope of the curve is similar to that of proliferation, showing the total loss near the age of maximum life potential (Ruiz-Torres et al 1999). Consequently, the interpretation is the same in

TABLE 2 Decrease of migration by age: Chemotaxis (basal and induced) of cells from young and old male donors

Age (years)

43

74

Number of experiments

3

3

Migrated cells:

Basal

930

36

540

43*

1 nM insulin

1110

165

740

106*/**

1 nM IGF1

1153

117

710

10*/***

Results using the Boyden chamber. *young:old P 5 0.05; **with basal young P 5 0.07; ***with basal young P 5 0.05.

Results using the Boyden chamber. *young:old P 5 0.05; **with basal young P 5 0.07; ***with basal young P 5 0.05.

both cases: during adulthood, increasing age decreases the sensitivity of SMCs to phenotypic change (Table 2). The high content of senescent cells in advanced age would remarkably diminish the risk for atherogenesis. The opposite would happen when relatively young SMCs coexist with risk factors such as hyperchol-esterolaemia and hyperinsulinaemia. This state corresponds to the age range within the 3rd and 5th decades according to our studies and in agreement with epidemiological results on cardiovascular degenerative diseases.

This work was made possible by a grant of the Fondo de Investigation Sanitaria (FIS), Spanish Ministry of Health, Nr 98/0177. The unpublished results described here were obtained with the collaboration of Raffaele Carraro, Rosario Lozano, Manuel Macia and Marcia Soares de Melo.

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