Some aspects of growth signal transduction in vascular smooth muscle cells

Abstract

Proliferation of vascular smooth muscle cells (VSMC) is a characteristic feature of repair following vascular injury and adaptation to increased intraluminal pressure such as occurs in arteriovenous fistulas and in pulmonary hypertension. The intimai smooth muscle accumulation in atherosclerosis, restenosis after angioplasty and in vein grafts is arguably a consequence of these same repair and haemodynamic adaptation mechanisms [1]. Intimai VSMC proliferation becomes of pathological significance when it causes an obstruction of normal flow and can then lead to heart failure (especially if in the pulmonary circulation), angina pectoris (if in the coronary circulation), cerebral ischaemia or peripheral organ ischaemia. These circulatory diseases together represent the most prevalent causes of morbidity and mortality in the developed world [2] and there is therefore an intense clinical and basic research effort aimed at improving therapy, one target for which is the design of clinically useful inhibitors of VSMC proliferation. Frustratingly, despite some 50 or so recent clinical trials of agents that have been shown to be effective in tissue culture or animal models, none of these has been of consistent benefit in preventing angioplasty restenosis in man [3], which indicates the need for more potent and selective agents. One promising approach to achieving such inhibitors is to intervene in the intracellular signalling pathways that mediate proliferation. Such a strategy rationally depends on knowledge of the signalling pathways themselves and the extent to which these are tissue-specific for VSMC. In this article, we will attempt to overview the relative limited information regarding these pathways in VSMC, relying where necessary on analogies with other cell types.