Atherosclerosis and the arterial smooth muscle cell

Author

Ross R, Glomset J Reference

Science 1973; 1BG: 1332-1339 Abstract

Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis.

Summary

In this paper, Russell Ross reviews the current data regarding the vascular smooth muscle cell in atherosclerosis. "Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis". At the time this paper was written, little was known about the genesis of atherosclerosis. Previous studies had demonstrated that blood pressure, smoking and plasma lipid concentrations could influence the development of clinical symptoms of atherosclerotic vascular disease but the sequence of pathological events at the cellular level was largely unknown.

Focal accumulation of intimal smooth muscle cells was argued to be critical to the early stages of atherosclerosis. Ross argued that "the accumulation of smooth muscle cells necessarily precedes or accompanies both the deposition of lipid and the accumulation of extracellular connective matrix, because the lipid deposits occur either within smooth muscle cells or outside them in association with connective tissue matrix components which are secretory products of smooth muscle cells". Ross stated that smooth muscle cell proliferation began when a breach of endothelial integrity occurred that would allow substances present in the plasma to stimulate cellular proliferation. Studies supporting these observations included the tendency of vascular smooth muscle cells to accumulate in the intima at arterial branch points, where endothelial permeability appeared to be increased. Stemerman and Ross had also demonstrated experimentally using macaques that vascular lesions could be induced by denuding the femoral artery vascular endothelium with balloon catheters. Three months after injury, the lesion contained as many as 15 layers of smooth muscle cells surrounded by collagen and immature elastic fibers. These lesions were described as identical in appearance to the "fibromusculoelastic" lesions seen in man. Ross also reviews evidence (in vitro and in vivo) that lipids appear to influence proliferation of vascular smooth muscle cells and that vascular smooth muscle cells are responsible for production of extracellular matrix.

Citation Count 986

Key message

Vascular smooth muscle cell proliferation plays a critical role in the development and growth of atherosclerotic lesions.

Strengths

The identification of vascular smooth muscle cells and the time course of proliferation and matrix production following vascular injury greatly enhanced the understanding of vascular lesion

Figure 1 Light micrographs demonstrating (a) a normal primate iliac artery (Mecaca nemestrina) (X550); (b) an iliac artery 3 months after de-endothelialization, showing a marked increase in intimal thickness due to accumulation of smooth muscle cells and extracellular matrix (X500); and (c) an iliac artery 6 months after de-endothelialization, by which time the intimal thickness had returned to one to two layers (X500). This sequence demonstrated the relative reversibility of an experimentally induced lesion in a monkey on a normal diet with normal concentration of plasma lipid.

Figure 1 Light micrographs demonstrating (a) a normal primate iliac artery (Mecaca nemestrina) (X550); (b) an iliac artery 3 months after de-endothelialization, showing a marked increase in intimal thickness due to accumulation of smooth muscle cells and extracellular matrix (X500); and (c) an iliac artery 6 months after de-endothelialization, by which time the intimal thickness had returned to one to two layers (X500). This sequence demonstrated the relative reversibility of an experimentally induced lesion in a monkey on a normal diet with normal concentration of plasma lipid.

formation. This work also identified the smooth muscle cell as a therapeutical target towards the prevention of vascular disease.

Weaknesses

Conclusion regarding cell types and cellular proliferation in atherosclerosis were based on studies of femoral artery injury in primates. The lesions that develop following arterial injury with balloon catheters (neointima) are fibrous and are not the same as those that occur in naturally occurring atherosclerosis. In addition, accurate means of identifying cell types in atherosclerotic plaques were not available at the time of this paper.

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