Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia

Abstract

Summary Coronary artery disease, leading to myocardial infarction and ischaemia, affects millions of persons and is one of the leading causes of morbidity and mortality worldwide. Invasive techniques such as coronary artery bypass grafting are used to alleviate the sequelae of arterial occlusion. Unfortunately, restenosis or occlusion of the grafted conduit occurs over a time frame of months to years with a gradual reduction in patency, especially in vein grafts. The events leading to intimal hyperplasia (IH) formation involve numerous cellular and molecular components. Various cellular elements of the vessel wall are involved as are leucocyte-endothelial interactions that trigger the coagulation cascade leading to localized thrombus formation. Subsequent phenotypic modification of the medial smooth muscle cells and their intimal migration is the basis of the lesion formation that is thought to be propagated by an immunemediated reaction. Despite intense scrutiny, the pathophysiology of IH remains an enigma. Although several growth factors, cytokines and numerous other biomolecules have been implicated and their relationship to prohyperplasia pathways such as the phosphatidyl-inositol 3-kinase (PI3K)-Akt pathway has been established, many pieces of the puzzle are still missing. An in-depth understanding of early vein graft adaptation and progression is necessary to improve the long-term prognosis and develop more effective therapeutic measures. In this review, we have critically evaluated and summarized the literature to elucidate and interlink the numerous established and emerging factors that play a key role in the development of IH leading to vein graft restenosis.

MiR‐152 reduces human umbilical vein endothelial cell proliferation and migration by targeting ADAM17

“…These inflammatory factors, including transforming growth factor-b (TGF-b), platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and vascular cell adhesion molecule (VCAM) may lead to proliferation and migration of vascular smooth muscle cells, intimal hyperplasia and induction of mononuclear and macrophage inflammatory infiltration or conversion into foam cells. This complex process ultimately results in atherosclerotic plaque formation and luminal stenosis [8][9][10].…”

“…Members of the ADAMs family (ADAM 8,9,10,12,15,17,19 and 28) are expressed widely in epithelial cells, smooth muscle cells and leukocytes [3,4]. As a well-known ectodomain sheddase, ADAM17 plays an important role in vascular physiological and pathological processes through regulating membrane-anchored protein maturation [5].…”

Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia

“…Unfortunately, pathological intimal hyperplasia (IH) ensues after these procedures largely due to the proliferation of vascular smooth muscle cells (VSMCs) in the media and their migration into the intima of the treated vessel (1)(2)(3). Such proliferation is induced by a number of growth-stimulatory signals that are activated by vascular injury and leads to high long-term failure rates of bypass surgery and angioplasty for treatment of cardiovascular disease (4)(5)(6)(7)(8)(9)(10)(11)(12). These failures often cause death and disability and may require repeated treatment by surgery or angioplasty.…”

Tacrolimus inhibits intimal hyperplasia in arterialised veins in rats

“…It has been shown that the level of intimal hyperplasia is directly linked to the degree of endothelial denudation, which, in vein grafts is caused by luminal distension during surgery, ischemia, damage at surgical anastomoses and continued physical trauma under arterial conditions (2)(3)(4). Moreover arterial tangential pressure, medial damage and thickening as well as shear stress changes and altered fl ow patterns are involved in the development of intimal hyperplasia (5)(6)(7).…”