The expression of VASP in endothelial cells and its role in endothelial proliferation have already been discussed in this chapter. Nevertheless, it seems important to underscore the possible role of VASP in the regulation of neointimal cell proliferation, which is regarded as a major factor in the development of arteriosclerotic diseases, such as spontaneous atherosclerosis, post-angioplasty restenosis and vein graft atherosclerosis. The tunica intima is the innermost endothelial layer of blood vessels, and neointimal cells are those endothelial cells that migrate and proliferate at injury sites in order to replenish the intimal layer. Abnormal neointimal proliferation is a key step towards the formation of the neointimal plaque: a pathological mass of endothelial and smooth muscle cells, macrophages, lymphocytes and lipid that causes the blood vessel restriction at the basis of arteriosclerosis. VASP has been shown to be overexpressed in the neointimal cell layer, resulting from the surgical endothelial denudation of rat carotid arteries (Monks et al. 1998). Moreover, a reduction of PKG expression and PKG-dependent phosphorylation of VASP has been reported in neointimal cells of atherosclerotic rabbit aortas (Melichar et al. 2004). Interestingly, overexpression of constitutively active PKG and the consequent hyperphosphorylation of VASP in rat aorta resulted in the reduction of neointimal proliferation following artery denudation (Sinnaeve et al. 2002). Taken together, the above studies suggest a rationale for the involvement of VASP in the endothelium-driven development of arteriosclerotic diseases. The modulation of VASP expression or phosphorylation in proliferating endothe-lial cells could therefore be regarded as an opportunity for therapeutic intervention, not only against neoplastic angiogenesis, but also against arteriosclerosis. Notably, the anti-platelet drug clopidogrel, already described in this report as an enhancer of VASP phosphorylation, has also been shown to improve endothelial function and flow-mediated artery dilation in coronary disease patients (Warnholtz et al. 2007). This effect of clopidogrel on artery function could be mediated by regulation of VASP and its function as modulator of neointimal proliferation.

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