Adventitial Activation in the Pathogenesis of Injury-Induced Arterial Remodeling

Abstract

Transplant vasculopathy is one of the major causes of chronic rejection after solid organ transplantation. The pathogenic mechanisms of transplant vasculopathy are still poorly understood. Herein, we summarize current evidence suggesting that activation of the tunica adventitia may be involved in the pathogenesis of transplant vasculopathy. Adventitia is an early responder to various vascular injuries and plays an integral role in eliciting vascular inflammation and remodeling. Accumulation of macrophages in the adventitia promotes the development of vascular remodeling by releasing a variety of paracrine factors that have profound impacts on vascular mural cells. Targeting adventitial macrophages has been shown to be effective for repressing transplantation-induced arterial remodeling in animal models. Adventitia also fosters angiogenesis, and neovascularization of the adventitial layer may facilitate the transport of inflammatory cells through the arterial wall. Further investigations are warranted to clarify whether inhibiting adventitial oxidative stress and/or adventitial neovascularization are better strategies for preventing transplant vasculopathy.

The Role of Fibroblasts in Atherosclerosis Progression

“…Several findings suggest a role of fibroblasts in all stages of atherosclerosis, from initial phase to fibrous cap and plaque formation. It is becoming evident that adventitial cells, including adventitial fibroblasts are one of the first cells to respond to injury and become activated in the initial stage of atherosclerosis, even before the formation of atherosclerotic lesions, supporting the new "outside-in" hypothesis [46,48].…”

“…Recent studies shed light on the implication of adventitial fibroblasts in different vascular pathologies, characterized by arterial remodeling and neointimal formation [43]. One of the most persistent findings in experimental in vitro and in vivo models is intensive adventitial remodeling, found very early in response to vascular injury or stress [46][47][48]. Adventitial remodeling in the vasculature has been characterized by increased proliferation of fibroblasts, which appear to be the first cells in the vessel wall that respond to different stimuli by their activation [49].…”

Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer‐like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure

“…Accumulating evidence, especially in the systemic circulation, has demonstrated that in many vascular injury models, changes in the adventitia precede those in other compartments and are in fact required for remodeling in response to various systemic vascular injuries. [77][78][79][80][81] This may be a consequence of the fact that the adventitia is a highly complex tissue and is poised to respond immediately to many of the stimuli involved in vascular remodeling. Unlike the intima and media, which are composed of single, although heterogeneous, types of cells, the adventitia contains, in addition to fibroblasts, leukocytes (including macrophages, dendritic cells, and mast cells), progenitor cells, nerves (sympathetic and parasympathetic), and lymphatics, as well as an additional blood supply, the vasa vasorum.…”

“…[81][82][83][84][85][86][87] In several studies in which blood vessels were injured from the intimal side (by wire or balloon), a rapid increase in cell proliferation was observed in the adventitia that exceeded that in the media at all time points after injury. 81,86,87 In these models, there was little accumulation of proliferating cells in the media and intima until at least seven days following an injury. In a large-animal model of hypercholesterolemia (porcine), it was shown that adventitial remodeling of the coronary artery, including adventitial angiogenesis, was an early change that preceded the development of changes in the intima and media.…”

Adenosine, Via A 2B Receptors, Inhibits Human (P-SMC) Progenitor Smooth Muscle Cell Growth

“…[2][3][4][5] In this context, CD34+/c-Kit+ mononuclear cells can differentiate (in response to growth factors like platelet derived growth factor, which is released during injury) into cells that express a SMC phenotype and subsequently contribute to neointimal formation by migrating to the site of injury and proliferating. [6][7][8][9][10] While the relative contribution of progenitor SMCs (P-SMCs) in neointimal formation remains an open question, studies conducted in the last decade suggest that P-SMCs derived from CD34+/c-Kit+ mononuclear cells contribute to neointimal thickening by 6% to 60%. 4,5 Although circulating bone marrow/hematopoietic-derived CD34+/c-Kit+ cells are postulated to be the key extravascular source of neointimal P-SMCs, 2,5 local c-Kit+ cells of vascular adventitial origin may also contribute to neointimal formation.…”