Preventing restenosis after angioplasty: a multistage approach

Abstract

Arterial reconstruction procedures, including balloon angioplasty, stenting and coronary artery bypass, are used to restore blood flow in atherosclerotic arteries. Restenosis of these arteries has remained a major limitation of the application of these procedures, especially in the case of balloon angioplasty. Post-angioplasty restenosis results from two major processes: neointimal formation and constrictive remodelling. Neointimal formation is initiated by arterial injury with a resultant loss of contractile phenotype in tunica media, leading to VSMC [vascular SM (smooth muscle) cell] migration from the tunica media to the intima. Migrated VSMCs contribute to the intimal thickening by the excessive synthesis of ECM (extracellular matrix) and proliferation. However, increased neointimal mass is not solely responsible for luminal narrowing. Inward constrictive remodelling is also considered as a major cause of delayed failure of angioplasty. At later stages after angioplasty, the increase in contractile forces leads to lumen narrowing. Recent studies show that SM contractile proteins are re-expressed in the neointima, concomitant with late lumen loss. Therefore one important question is whether the restoration of contractile phenotype, which can suppress VSMC migration, is favourable or detrimental. In this review, the importance of viewing restenosis as a multistage process is discussed. Different stages of restenosis occur in a sequential manner and are related to each other, but in each stage a different strategy should be taken into consideration to reduce restenosis. Defining the role of each process not only reshapes the current concept, but also helps us to target restenosis with more efficacy.

Hyperglycemia has no effect on development of restenosis after percutaneous transluminal angioplasty (PTA) in a diabetic rabbit model

“…In the acute phase of restenotic plaques, arterial injury evokes loss of the contractile phenotype in the tunica media, leading to migration of SMCs from the media toward the intima. Then the presence of these SMCs result in the intimal thickening of the restenosis via the excessive synthesis of ECM and cell proliferation (Zargham 2008). Thus, the migration of vascular SMCs from the media to the intima may be the principal step in the development of restenosis (Marx et al 2011), and restenotic lesion-activated specific signaling pathways leading to the migration of SMCs may play essential roles in this process.…”

“…Therefore, hyperglycemia, which accelerates the process of atherosclerosis mainly by promoting So what accounts for rapid formation of restenotic plaques? Unlike atherosclerotic plaques in which WBCs and inflammation are major mediators (Roque et al 2002, Edlin et al 2009, Barbieri et al 2013, Nagareddy et al 2013, restenotic plaques is typically hypercellular with foci of vascular SMCs and extracellular matrix (ECM) (Zargham 2008, Muthiah et al 2014 (Fig. 4).…”

Protease-Activated Receptor-1 Antagonist F 16618 Reduces Arterial Restenosis by Down-Regulation of Tumor Necrosis Factor α and Matrix Metalloproteinase 7 Expression, Migration, and Proliferation of Vascular Smooth Muscle Cells

“…Platelet-derived growth factor (PDGF) is a mediator of SMC de-differentiation, migration and proliferation (Zargham, 2008). Its expression is up-regulated by the transcription factor early growth response-1 (Egr-1), which is rapidly induced at the endothelial wound edge after balloon angioplasty (Khachigian, 2006).…”

“…In vivo, de-differentiation of vascular SMCs evidenced by loss of their contractile phenotype stimulates their migration and proliferation (Zargham, 2008). To explore whether the F 16618 treatments prevented restenosis by inhibition of SMC dedifferentiation, we quantified the mRNA expression of the contractile protein smoothelin 24 h after angioplasty.…”

“…Wound healing after vascular injury, and in particular restenosis after balloon angioplasty and stenting, results from different processes such as inflammation, smooth muscle cell (SMC) de-differentiation leading to SMC migration and proliferation, and constrictive remodeling (Muto et al, 2007;Zargham, 2008). In fact, localized loss of endothelium and subendothelial structures allows the direct contact of This work was funded in part by Pierre Fabre Laboratories, a privately held drug discovery company, and the Institut National de la Santé et de la Recherche Médicale.…”