Angiogenesis, Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor-BB Expression, Iron Deposition, and Oxidation-Specific Epitopes in Stented Human Coronary Arteries

Abstract

Abstract-Pathogenesis of in-stent restenosis remains poorly understood because information from human histopathologic studies is scarce. We used an improved saw-grinding and cutting method on methacrylate-embedded samples containing metal stents, which allows in situ hybridization and immunohistochemical analysis of in-stent restenosis. Twenty-one samples were collected 3 hours to 3 years after stenting from 6 patients aged 36 to 81 years. Except in very early samples collected within hours after the stent deployment, neovascularization was present in all segments studied. At advanced stages, extensive neovascularization was located mainly at the luminal side of the stent struts and was only rarely accompanied by inflammatory cells. The neovessels colocalized with vascular endothelial growth factor (VEGF)-A mRNA and protein expression as well as with iron deposits and oxidation-specific epitopes, which imply the presence of chronic oxidative stress. VEGF-A expression was detected in the same areas containing macrophages, endothelial cells, and, to a lesser extent, smooth muscle cells, which also showed platelet-derived growth factor-BB expression. We conclude that in-stent restenosis features neovascularization, VEGF-A and platelet-derived growth factor-BB expression, and iron deposition, which is most probably derived from microhemorrhages. These mechanisms may play an important role in the development of neointimal thickening and could provide useful targets for the prevention and treatment of in-stent restenosis. Key Words: in-stent-restenosis Ⅲ immunohistochemistry Ⅲ in situ hybridization Ⅲ pathology Ⅲ methylmethacrylate embedding P ercutaneous transluminal coronary angioplasty (PTCA) is the treatment of choice in short single coronary lesions. Acute complications, dissections, and early recoil can be treated or avoided with intracoronary stents, which also reduce the incidence of late restenosis. Nevertheless, angiographic restenosis is seen in 20% to 30% of ideal lesions treated with stents. 1,2 The angiographic restenosis rate with more complex lesions is even higher. 3 Treatment of in-stent restenosis by balloon dilation, rotablation, and coronary atherectomy leads to unsatisfactory results in at least 50% of the cases. 4 Thus, prevention of in-stent restenosis is an important goal. See coverIn-stent restenosis is thought to be a reparative process resembling wound healing, involving a cascade of traumatic, thrombotic, granulating, and proliferative phases as well as late remodeling, with final accumulation of smooth muscle cells and matrix components. 5,6 Glycoprotein IIb/IIIa antagonists aiming at blocking early platelet deposition/thrombus formation and the proliferation and migration of smooth muscle cells reduced but failed to fully inhibit in-stent restenosis. 7,8 The amount of medial damage and stent oversizing have been shown to be correlated with the degree of in-stent restenosis, suggesting that the extent of vessel trauma plays a crucial role in in-stent restenosis. 9,10 One of the major probl...

Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism

“…Inflammatory response after angioplasty and stenting is one of the key elements that lead to neointimal hyperplasia and restenosis. [20][21][22][23] NO is a known inhibitor of several cytokine-mediated processes that participate in the inflammatory response leading to restenosis. NO regulates MCP-1 in endothelial and SMCs.…”

Marriage of resistance and conduit arteries breeds critical limb ischemia

“…Improved blood flow may result from increased density of nutritive arteries in the ischemic limb tissue or from formation of bypass channels that divert blood around an obstruction (24,59,79). In contrast, angiogenesis within atherosclerotic plaque tissue is considered to be detrimental, because new vessels in this location are highly susceptible to rupture, and intraplaque hemorrhage is one of the key factors leading to plaque deterioration and instability (8,41). VEGF is localized to these intraplaque vessels (8,41), and in a cholesterol-fed rabbit model, administration of recombinant VEGF increased atherosclerotic plaque area (16).…”

Mast Cells in Neovascularized Human Coronary Plaques Store and Secrete Basic Fibroblast Growth Factor, a Potent Angiogenic Mediator

“…14 Moreover, the extravasated erythrocytes lead to local iron deposition and thereby lead to increased oxidative stress in the atheroma. 29 Besides being associated with plaque neovessels, bFGF may contribute to plaque remodeling by stimulating the proliferation of SMCs. Because bFGF lowers the capacity of SMCs to synthesize collagen, 30 MC-derived bFGF may potentially have plaque-weakening effects.…”