Nitric oxide and the proliferation of vascular smooth muscle cells.

Abstract

Time for primary review 13 days. Vascular smooth muscle cell (VSMC) proliferation is an important component of vessel wall remodelling in response to injury, for example, after angioplasty or vein grafting, and during atherosclerosis formation. Endothelium-derived nitric oxide (NO) production is both a tonic and an induced regulator of blood vessel tone [1–3]. Its function is impaired by atherosclerosis and, more significantly, by atherogenic risk factors, including hypercholesterolaemia, homocysteinaemia, diabetes, smoking and high blood pressure, even before the appearance of overt atherosclerosis [4–6] Endothelial NO production is dysfunctional after balloon injury and in vein grafts at the time when VSMC proliferation and neointima formation is progressing [5,6]. It has been tempting, therefore, to propose a causal relationship between impaired NO production and increased VSMC proliferation. If so, this might explain, in part, the association between endothelial dysfunction and atherogenesis. The primary purpose of this review is to discuss critically the evidence to support such an hypothesis. We will also go on to consider the molecular mechanisms that might underlie the inhibitory effects of NO on VSMC proliferation, with the following important caveats. Firstly, any direct action of NO on an increase in VSMC numbers may be mediated at a variety of levels, for example, on the signal transduction pathways, on energy production or by promoting cell death. Secondly, in the more complex in vivo models, effects of NO on endothelial cells (ECs), platelets and inflammatory cells, rather than directly on VSMCs may be responsible for modulating VSMC proliferation. Thirdly, NO is highly unstable, with a half-life measured in seconds [2,7,8]. It reacts rapidly with oxygen species (O2, O2− and H2O2) to produce, nitrite, nitrate or the highly reactive species, peroxynitrite (ONOO) and with thiol groups to produce nitrosothiols [9]. … * Corresponding author. Tel.: +44-117-928-3154; fax: +44-117-929-9737 j.y.jeremy{at}bristol.ac.uk