Key Features of the Intragraft Microenvironment that Determine Long-Term Survival Following Transplantation

Abstract

In this review, we discuss how changes in the intragraft microenvironment serve to promote or sustain the development of chronic allograft rejection. We propose two key elements within the microenvironment that contribute to the rejection process. The first is endothelial cell proliferation and angiogenesis that serve to create abnormal microvascular blood flow patterns as well as local tissue hypoxia, and precedes endothelial-to-mesenchymal transition. The second is the overexpression of local cytokines and growth factors that serve to sustain inflammation and, in turn, function to promote a leukocyte-induced angiogenesis reaction. Central to both events is overexpression of vascular endothelial growth factor (VEGF), which is both pro-inflammatory and pro-angiogenic, and thus drives progression of the chronic rejection microenvironment. In our discussion, we focus on how inflammation results in angiogenesis and how leukocyte-induced angiogenesis is pathological. We also discuss how VEGF is a master control factor that fosters the development of the chronic rejection microenvironment. Overall, this review provides insight into the intragraft microenvironment as an important paradigm for future direction in the field.

Keywords: allograft rejection; allograft vasculopathy; angiogenesis; chronic allograft rejection; endothelial cell; hypoxia; microvascular injury; vascular endothelial growth factor.

Figure 1

Cartoon illustrating the interplay between alloimmunity and the intragraft microvasculature. (A) Following transplantation, alloimmune inflammatory responses target the graft vascular endothelium resulting in the destruction of microvessels, which in turn leads to local hypoxia and tissue injury. (B) Alloimmune inflammatory responses may also stimulate endothelial cell proliferation and promote leukocyte-induced angiogenesis within allografts. The local delivery of the pro-inflammatory and pro-angiogenic factor vascular endothelial growth factor (VEGF) is central to this response. Pathological leukocyte-induced angiogenesis results in the formation of abnormal networks of capillaries that lead to chaotic blood flow patterns and paradoxically results in local hypoxia. Thus, local tissue hypoxia is the end result of acute events and direct targeting of the graft endothelial cells (A) as well as inflammation and the associated leukocyte-induced angiogenesis (B).

Figure 2

Cartoon illustrating a mechanism of tissue fibrosis associated with allograft rejection. During inflammation, pathological angiogenesis, and/or local hypoxia can lead to pericyte loss. Under normal conditions homeostatic repair occurs under the influence of protective growth and survival factors. In contrast, when the inflammatory microenvironment is sustained, the loss of pericytes serves as a precedent for endothelial-to-mesenchymal transition (EndMT), where endothelial cells become denuded from their basement membrane and migrate along with pericytes into the surrounding tissue. Although still under debate, it is reported that the presence of TGFβ, inflammatory cytokines, and hypoxia enables dissociated pericytes and/or endothelial cells to dedifferentiate into collagen-secreting fibroblasts, which in turn results in fibrosis and scarring.