Resveratrol and vascular smooth muscle cells

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Vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of atherosclerotic lesions, since their proliferation and migration are critical events for progressive intima thickening and development of arterial wall sclerosis [73]. OxLDL can also promote the proliferation of the smooth muscle cells (SMC) which are in part resident intimal cells that preceded the lesions and in part their progeny that arose as a response to various stimuli (e.g. lipid accumulation, disruption of intimal sructure). Intima SMC accumulate large amounts of cholesterol esters and become foam cells (figure 4). Inhibition of VSMC proliferation may have a beneficial effect in retarding development of atherosclerotic disease.

Resveratrol could delay atherogenesis by inhibition of VSMCs proliferation [74, 75]. Indeed, resveratrol is able to reduce SMCs proliferation induced by diverse mitogens such as serum, endothelin and PGDF. The antimitogenic effects of resveratrol are not mediated by the induction of apoptosis, but appear to be related to a G1®S block in cell cycle traverse [76, 77] and the DNA synthesis [75]. In fact, resveratrol leads to a reversible arrest in early S phase of the VSMC cycle. About the molecular mechanism, it exists a controversery: Haider et al have shown that the VSMC cycle arrest was accompanied by an accumulation of an hyperphosphorylated retinoblastoma protein, a decrease of cellular levels of the cyclin-dependent kinase inhibitors p21(Cip1), p27(Kip1), and an enhancement of phosphorylated of p53 protein [77]. On the contrary, Mnjoyan and Fujise have shown that p21 and p53 are increased but this effect depends of resveratrol concentration [75]. Indeed, at lower concentration (6.25-12.5 µM), resveratrol inhibits VSMCs proliferation without apoptosis described by Haider et al, but at higher concentration (25µM), resveratrol induces apoptosis in serum-stimulated VSMCs but not in quiescent VSMCs. These results suggest that resveratrol may be able to selectively eliminate abnormally proliferating VSMCs of the arterial walls in vivo. Resveratrol can also inhibits VSMCs proliferation induced by AGEs (Advanced Glycation End-product) of plasma proteins and/or matrix proteins which are mediators implicated in various vascular complications [78]. AGEs increase coagulation through various mechanisms involving the vascular endothelium and platelet activation [79]. AGEs also increase DNA synthesis and propyl hydroxylase activity, a marker of collagen synthesis in stroke-prone spontaneously hypertensive rats (SHRSP) or Wistar-Kyoto rats (WKY) VSMCs. These phenomenon are inhibited by resveratrol in animal experimental model [80]. In this same perspective of fighting against atherosclerosis process, it has been shown that the inhibition of pulmonary artery endothelial cells proliferation by resveratrol is correlated with the suppression of cell progression through S and G2 phases of the cell cycle [81, 82].