Abstract
Basic fibroblast growth factor (FGF2) is a potent mitogen for medial smooth muscle cells and is necessary for their proliferation after balloon catheter injury; however, intimal smooth muscle cells do not require FGF2 for their proliferation, and they respond only weakly to exogenous FGF2. The present study examined the activation of extracellular signal-regulated kinase (ERK) signaling as well as the expression and activity of cell cycle proteins in FGF2-stimulated intimal smooth muscle cells. FGF2 activates ERKs 1 and 2, and Western blot analysis showed that cyclin D, cyclin E, and cyclin-dependent kinase (CDKs) 2 and 4 were expressed in intimal smooth muscle cells after FGF2 infusion. FGF2 stimulation, however, did not lead to phosphorylation of the retinoblastoma protein (Rb), CDK 2 activation, or expression of cyclin A. Western blot analysis showed that intimal smooth muscle cells express elevated levels of the cell cycle inhibitors p15(INK4b) and p27(Kip1), compared with medial smooth muscle cells, and that FGF2 stimulation does not reduce the level of these inhibitors. These studies suggest that despite activation of ERKs 1 and 2 and expression of the cell cycle activators, cyclin D and cyclin E, high levels of cell cycle inhibitors may inhibit cell cycle transit in FGF2-stimulated intimal smooth muscle cells.
Highlights
Excessive growth of vascular smooth muscle cells is an important component in the development of atherosclerotic lesion and in restenosis
Activation of the extracellular signal-regulated kinase (ERK) is required for FGF2-stimulated proliferation in several different cell types, and recently we have shown that the ERK signaling pathway is activated following balloon catheter denudation of the rat carotid artery and that ERK activity is required for smooth muscle cell proliferation following this injury [10]
FGF2 stimulation requires activation of cytoplasmic signaling molecules such as the ERKs and PI 3-kinase to induce proliferation, the resultant signaling must lead to activation of the cyclin-dependent kinases (CDKs) in order for cells to progress through the G1 phase of the cell cycle and into S phase
Summary
Excessive growth of vascular smooth muscle cells is an important component in the development of atherosclerotic lesion and in restenosis. Our data show that FGF2 stimulation of smooth muscle cells in established intimal lesions activates both the ERKs and PI 3-kinase and increases cyclin D expression but does not lead to phosphorylation of the retinoblastoma protein, activation of CDK 2, or increased expression of cyclin A. In these same arteries, high levels of the cyclin-dependent kinase inhibitors p27Kip and p15INK4b were noted, and we believe that their presence is responsible for the attenuation of FGF2-induced proliferation
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