Vascular Remodeling in Transplant Vasculopathy

Abstract

Abstract-As therapeutic strategies to prevent acute rejection progressively improve, transplant vasculopathy (TV)constitutes the single most important limitation for long-term functioning of solid organ allografts. In TV, allograft arteries characteristically develop severe, diffuse intimal hyperplastic lesions that eventually compromise luminal flow and cause ischemic graft failure. Traditional immunosuppressive strategies that check acute allograft rejection do not prevent TV; indeed 50% of transplant recipients will have significant disease within five years of organ transplantation, and 90% will have significant TV a decade after their surgery. TV can involve the entire length of the transplanted arterial bed, including penetrating intraorgan arterioles. Indeed, the luminal narrowing of such penetrating vessels may be the most functionally significant because arterioles represent the major contributors to tissue vascular resistance. Because of the diffuseness of TV involvement in the allograft vascular bed, the only currently definitive therapy requires re-transplantation. Nevertheless, as we better understand the pathogenesis and critical mediators of these lesions, pharmacological advances can be anticipated. Other articles in this thematic review series focus on the specifics of the inciting injury, the cytokines and chemokines that drive TV development, and the nature of the recruited cells in TV lesions, as well as the pathogenic similarities between TV and other vascular lesions such as atherosclerosis. This review focuses on the mechanisms of vascular wall remodeling in TV, including the intimal accumulation of smooth muscle-like cells and associated extracellular matrix, medial smooth muscle cell degeneration, and adventitial fibrosis. A brief overview highlights the aneurysmal changes that can accrue when vessel wall inflammation has a cytokine profile distinct from the typical proinflammatory interferon-␥-dominated milieu. We and others showed that the development of TV requires the archetypal Th1 cytokine interferon-␥ (IFN-␥); TV lesions do not develop in the setting of congenital absence or monoclonal antibody blockade of IFN-␥. 8,11,12 In an elegant experiment using donor human arterial grafts in immunodeficient mice, Tellides et al further demonstrated that IFN-␥ alone, without associated inflammation, is sufficient to induce TV-like lesions. 13 However, despite almost a decade of subsequent investigation, the relevant IFN-␥ pathway(s) underlying TV development remain ill defined. As discussed elsewhere in this review series (G. Tellides and J. Pober), the potent pleiotropic cytokine IFN-␥ affects the activation state of multiple cell types, and also regulates major histocompatibility complex and costimulator molecule expression and the production of cytokines, chemokines, adhesion molecules, and extracellular matrix (ECM). Classically a product of Th1 and Tc1 T-cell subsets as well as natural killer (NK) cells, IFN-␥ also can be produced by activated macrophages (forming an autocrine loop), 14...

Induction of Endothelial Nitric Oxide Synthase Expression by IL-17 in Human Vascular Endothelial Cells: Implications for Vascular Remodeling in Transplant Vasculopathy

“…TV in its full development is characterized by intimal thickening and luminal narrowing of allograft arteries, ultimately leading to acute occlusive events and associated tissue infarction. The pathogenesis of TV involves two main arterial changes: structural changes leading to thickening of the intima and vasomotor dysfunction characterized by defective arterial vasodilation and/or aberrant vasoconstriction (14). Thickening of the arterial intima in TV is caused by immunemediated damage and dysfunction of the graft endothelium, which leads to leukocyte and smooth muscle cell migration into this layer of the vessel wall (15).…”

Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular Smooth Muscle Cell Phenotype

“…10,11 The unabated expansion of VSMCs can lead to pathophysiologic complications, such as clinical restenosis after percutaneous coronary intervention, 12,13 arteriovenous shunt failure, 14,15 and transplant vasculopathy. 16 Generally, VSMCs are programmed to avoid this excessive reparative response, because they possess the capacity to sense and respond to extracellular and intracellular cues that trigger the reversion to the contractile phenotype.…”

Increased epicardial adipose tissue volume is associated with PR interval prolongation

“…It has also been demonstrated that C-reactive protein (CRP) and cytokines (such as IL-6 and platelet-activating factor) are associated with arrhythmias through the modulation of ion channel function [11,12] and the aggravation of sympathetic tone [11]. Hence, elevated levels of inflammatory mediators may provoke vasculopathy, myocardial fibrosis, sympathetic hyperactivity and ion channel malfunction [12][13][14][15], which can lead to a high risk of cardiac arrhythmias and even death.…”