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Mitogen-activated protein kinase and proliferation of human vascular smooth muscle cells
S Mii1, R A Khalil, K G Morgan
1Department of Surgery (Division of Vascular Surgery), Beth Israel Hospital, Boston, Massachusetts, USA.
Abstract:
The intracellular messenger mitogen-activated protein kinase (MAPK) is activated in vascular smooth muscle cells (SMC) by various growth factors as well as by agonists that have no proliferative effect. We explored the hypotheses that SMC proliferation is associated with a specific pattern of MAPK activation by evaluating the kinetics of MAPK activation and tyrosine phosphorylation and the intracellular location of MAPK in SMC following addition of agonists of varying mitogenic potential. A peak in MAPK activation and tyrosine phosphorylation occurred 3-10 min after the addition of agonists to SMC derived from human saphenous vein (early phase), followed by a plateau of activity, which was variable in duration (late phase). A correlation was not found between mitogenicity and the degree to which MAPK became activated or tyrosine phosphorylated in the early phase. However, the duration of MAPK activation and tyrosine phosphorylation correlated strongly with the ability of agonists to stimulate SMC proliferation. Nuclear translocation of MAPK was associated with SMC proliferation, although the degree to which each agonist induced nuclear translocation did not parallel its mitogenic potential. The relative dependency of all three events on protein kinase C differed for each agonist and was greater in the late versus the early phase. Thus, in human SMC, nuclear translocation of MAPK and prolonged activation and tyrosine phosphorylation of MAPK are associated with growth factor-induced mitogenesis.
Insights
Prolonged mitogen-activated protein kinase (MAPK) activation and nuclear translocation in vascular smooth muscle cells (SMC) are linked to cell growth. The duration, not the initial intensity, of MAPK signaling predicts SMC proliferation.
Area of Science:
- Cell Biology
- Molecular Biology
- Vascular Biology
Background:
- Mitogen-activated protein kinase (MAPK) is a key intracellular signaling molecule.
- MAPK activation in vascular smooth muscle cells (SMC) occurs with mitogenic and non-mitogenic stimuli.
- The specific patterns of MAPK activation related to SMC proliferation remain unclear.
Purpose of the Study:
- To investigate the relationship between specific patterns of MAPK activation and SMC proliferation.
- To evaluate the kinetics, intracellular localization, and tyrosine phosphorylation of MAPK in response to agonists with varying mitogenic potential.
Main Methods:
- Human saphenous vein SMC were treated with agonists of differing mitogenic capacity.
- Kinetics of MAPK activation, tyrosine phosphorylation, and nuclear translocation were measured.
- The role of protein kinase C in these signaling events was assessed.
Main Results:
- MAPK activation and tyrosine phosphorylation showed an early peak (3-10 min) followed by a variable late phase.
- The duration of MAPK activation and tyrosine phosphorylation, not the early phase intensity, correlated with SMC proliferation.
- Nuclear translocation of MAPK was associated with proliferation, but its degree did not directly parallel mitogenic potential.
Conclusions:
- Prolonged MAPK activation and tyrosine phosphorylation are key indicators of SMC mitogenesis.
- Nuclear translocation of MAPK is associated with growth factor-induced SMC proliferation.
- Protein kinase C dependency varies between early and late phases of MAPK signaling.