Smooth Muscle Cell Heterogeneity

Abstract —Early morphological and biochemical studies indicated that vascular smooth muscle cells (VSMCs) exhibited two distinct phenotypes and that a change from the contractile to the synthetic phenotype was a prerequisite for progression of vascular disease. More recently, it has become evident that these phenotypes probably represent the extremes of a spectrum of phenotypes that may coexist in the vessel wall, which are dictated by their environment and functional requirements and which reflect differing patterns of gene expression. Therefore, knowledge of the key factors that regulate these patterns of gene expression is likely to lead to the ability to manipulate VSMC phenotype. However, before such factors can be identified, the relationship between VSMC gene expression and VSMC phenotype must first be established. We therefore undertook a differential screen of cDNA from VSMCs in vitro to provide a bank of gene markers that could be used under a variety of circumstances to define VSMC phenotype in terms of the pattern of genes expressed. Using this approach, we have found that the pattern of gene expression that occurs during neointima formation in the balloon-injured rat carotid artery is very similar to that seen at a specific period in the developing aorta of the early neonate and is characterized by coexpression of genes for both contractile and matrix proteins. Furthermore, recent studies have shown that VSMCs isolated at different stages of aortic development can stably maintain different phenotypic characteristics in cell culture. The use of these cells in transfection experiments with SM-specific promoter–chloramphenicol acetyltransferase reporter constructs may enable us to determine what regulates the pattern of gene expression in different VSMC phenotypes. Such studies may ultimately lead to the identification of transcription factors responsible for determining VSMC phenotype and may therefore provide targets for therapy aimed at manipulating VSMC gene expression in vascular disease.