How an atherosclerotic plaque evolves from minimal diffuse intimal hyperplasia to a critical lesion is not well understood. Cellular proliferation is a relatively infrequent and modest event in both primary and restenotic coronary atherectomy specimens, leading us to believe that other processes, such as the formation of extracellular matrix, cell migration, neovascularization, and calcification might be more important for lesion formation. The investigation of proteins that are overexpressed in plaque compared with the normal vessel wall may provide clues that will help determine which of these processes are key to lesion pathogenesis. One such molecule, osteopontin (OPN), is an arginine-glycine-aspartate-containing acidic phosphoprotein recently shown to be a novel component of human atherosclerotic plaques and selectively expressed in the rat neointima following balloon angioplasty. Using in situ hybridization and immunohistochemical I dentifying the processes and molecular mediators of atherosclerotic plaque formation are currently areas of intense investigation. While focal smooth muscle cell (SMC) accumulations have been considered a hallmark of atherosclerosis and restenosis, 15 recent data suggest that the frequency of SMC replication in plaques is low. 6 -7 Thus, smooth muscle proliferation may not be a dominant event in lesion progression. Instead, other processes, such as cell migration, extracellular matrix formation, neovascularization, and calcification may be important pathophysiological events that are possibly linked to the expression of genes unique to atherosclerotic plaque and not found in the normal vessel wall. Examples of molecules that are overexpressed in the plaque compared with the normal vessel wall include platelet-derived growth factor-A, 8 bone morphogenetic protein-2a, 9 the major histocompatibility complex class II (la) antigen, 10 and the focus of the current study, osteopontin (OPN)." Although the mechanisms by which these genes are regulated are unknown, it is plausible to consider that SMC diversity plays a role, since plaque SMCs show a spectrum of phenotypes ranging from well differentiated (ie, containing abundant smooth muscle contractile proteins) to relatively undifferentiated (ie, containing little contractile apparatus but increased protein synthetic machinery), with the latter being present in the greatest numbers and commonly implicated in lesion progression.
12Using a differential cloning strategy, we have identified OPN, as well as several other genes (eg, collagen 1 [o-l], elastin), that are overexpressed in the rat neointima in vivo and that distinguish rat vascular SMC phenotypes in vitro.1314 OPN is an arginine-glycineaspartate-containing acidic phosphoprotein normally restricted to bone matrix, kidney, and epithelial lining cells and has been implicated in bone morphogenesis, tumor metastasis, bacterial resistance, immune function, and renal physiology. 15 In vitro, OPN serves as an adhesive substrate for both vascular smooth muscle and endothelial...