A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies.

Growth regulatory properties of endothelins

Resolved and unresolved issues in the prevention and treatment of coronary artery disease: A workshop consensus statement☆☆☆

The smooth muscle cell is the sole cell type normally found in the media of mammalian arteries. In the adult, it is a terminally differentiated cell that expresses cytoskeletal marker proteins like smooth muscle α-actin and smooth muscle myosin heavy chains, and contracts in response to chemical and mechanical stimuli. However, it is able to revert to a proliferative and secretory active state equivalent to that seen during vasculogenesis in the fetus, and this is a prerequisite for the involvement of the smooth muscle cell in the formation of atherosclerotic and restenotic lesions. A similar transition from a contractile to a synthetic phenotype occurs when smooth muscle cells are established in culture. Accordingly, an in vitro system has been used extensively to study the regulation of differentiated properties and proliferation of these cells. During the first few days after seeding, the cells are reorganized structurally with a loss of myofilaments and formation of a widespread endoplasmic reticulum and a prominent Golgi complex. In parallel, they lose their contractility and instead become competent to divide in response to a large variety of mitogens, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). After entering the cell cycle, they start to produce these and other mitogens on their own, and continue to replicate in the absence of exogenous stimuli for a restricted number of generations. Furthermore, they start to secrete extracellular matrix components such as collagen, elastin, and proteoglycans. The mechanisms that control this change in morphology and function of the smooth muscle cells are still poorly understood. Adhesive proteins such as fibronectin and laminin apparently have an important role in determining the basic phenotypic state of the cells and exert their effects via integrin receptors. The proliferative and secretory activities of the cells are influenced by a multitude of growth factors, cytokines, and other molecules. Although much work remains before an integrated view of this regulatory machinery can be achieved, there is no doubt that the cell culture technique has contributed substantially to our knowledge of smooth muscle differentiation and growth. At the same time, it has been crucial in exploring the role of these cells in vascular disease and developing new therapeutic strategies to cope with major causes of human death and disability.

Differentiated Properties and Proliferation of Arterial Smooth Muscle Cells in Culture

The suggestion that smooth muscle cell proliferation contributes to hypertension, atherosclerosis, and restenosis after angioplasty has led to a growing interest in the use of drugs to inhibit this process. This review summarizes pharmacological studies of smooth muscle cell proliferation in vitro and in vivo and identifies specific mediators of proliferation that are implicated by drugs binding with high affinity to enzymes or receptors.

Maria Sjölund

Papers

The calcium antagonist nifedipine inhibits arterial smooth muscle cell proliferation.