ABSTRACT
The arterial wall is composed of the intima, media, and adventitia. The intima consists of the endothelium and, in some species, 1-2 layers of SMCs as well (Schwartz et al., 1995a). These cells are clearly demarcated from the SMCs of the media by the internal elastic lamina. Vascular injury stimulates the development of a “neointima” at the site of injury. While the etiology of intimal hyperplasia is multifactorial, the most common initiating event is the dirsuption of the endothelium (Gibbons and Dzau, 1996). The endothelium is the normal source of regulatory molecules that modulate its own physiologic responses and the growth of the underlying SMCs while minimizing the accessibility of inflammatory cells
to the vascular wall (Gibbons and Dzau, 1996). Injury characteristically results in the loss of the endothelium and is quickly followed by platelet adhesion with thrombus formation (Schwartz et al., 1995a). An inflammatory response is initiated, marked by macrophage and lymphocyte infiltration. Vascular healing has been well characterized in rodents (Schwartz et al., 1995b; Clowes et al., 1983). About 24 hours after the insult, medial SMC proliferation can be detected (Clowes et al., 1983). This “first wave” replication is mediated by basic fibroblast growth factor (bFGF) released locally by the injured SMCs (Olsen et al., 1992; Lindner and Reidy, 1991). Basic FGF is a potent mitogen for both SMCs and endothelial cells. Inhibition of this first wave response using antisense oligonucleotides directed against cell cycle genes (Simmons et al., 1994; Biro et al., 1993) diminishes intimal hyperplasia. The “second wave”, occurring between post-injury days 3-14 (Clowes et al., 1983), consists of SMC migration across the internal elastic lamina to form the neointima. The cellular signals that mediate SMC migration include platelet-derived growth factor (PDGF) (Ferns et al., 1991; Jackson et al., 1993), transforming growth factor (TGF ) (Schwartz et al., 1995), and angiotensin II (Prescott et al., 1991). Following SMC migration, neointimal SMCs undergo extensive proliferation and deposit extracellular matrix (Clowes et al., 1986). This “third wave” response accounts for the most significant increase in neointima thickness. The signals regulating this third phase of vascular healing are still under investigation.
