[Mechanisms of re-stenosis after angioplasty]

Restenosis post angioplasty is a segmentally limited, wound healing response to a circumscript traumatization of the vascular wall associated with the therapeutic intervention, which also comprises residual or recoiling plaque components at the time of initial revascularization. Studies with animal models and the analysis of human plaque tissue harvested by autopsy or atherectomy indicate a cascade-like course of this wound healing reaction, in which initially different cell types such as thrombocytes, endothelial cells, monocytes/macrophages and smooth muscle cells (SMCs), later predominantly SMCs are involved. In the first phase of inflammation, angioplasty as a multifactorial stimulus induces a sequence of (a) destruction of endothelial and subendothelial structures, (b) traumatization of medial regions with rupture of the internal elastic lamina, (c) exposition of thrombogenic factors such as collagen or tissue factor, (d) stretching of smooth muscle cells with subsequent expression of proto-oncogens (c-fos, c-myc, c-myb), (e) release of growth factors from cells of the bloodstream, endothelial cells and SMCs by direct traumatization and segmental thrombus formation, and (f) thrombin production with autocatalytic activation of the SMC thrombin receptor. Overlapping the inflammation period, granulation begins 3 days after angioplasty. Proteinases such as plasmin as well as collagenases induce the disintegration of extracellular matrix structures, thereby modulating plaque formation, and lead to an organelle-rich SMC phenotype within the intima and media. The phenotypic alteration of SMCs is considered to be the prerequisite for mitogenic and migratory stimulation. This stage shows different expression patterns of growth factors and their receptors; however, there is only limited knowledge about spatiotemporal and maximal expression as well as their coordination for human vascular wall tissue (PDGF, PDGF-R, EGF-R, FGF, FGF-R, TGF-beta). Overlapping with the granulation period, induction of different components of the extracellular matrix occurs 1-2 weeks after angioplasty, possibly mediated by TGF-beta (phase of matrix formation). Smooth muscle cells produce and secrete matrix proteins such as tenascin, fibronectin, collagens and proteoglycans, and thereby induce a marked increase of the neointimal plaque volume. Angiographic restenoses of coronary and peripheral arteries histologically exhibit tissue with high cellularity (> 500 cells/mm2), associated with SMC activity markers such as PCNA or NMMHC-B. Proliferative and migratory activities of these cells in vitro are augmented by a factor of 2 to 3 as compared to those from chronic primary lesions. Transmission electron microscopic analysis proves that within the media a nearly complete re-differentiation of SMCs occurs, whereas intimal SMCs persist in the intermediate phenotype.(ABSTRACT TRUNCATED AT 400 WORDS)