Abstract
Fibrocytes are myeloid lineage cells implicated in wound healing, repair, and fibrosis. We previously showed that fibrocytes are mobilized into the circulation after vascular injury, including the immune-mediated injury that occurs after allogeneic transplantation. A common response to inflammatory vascular injury is intimal hyperplasia (IH), which, alongside vascular remodeling, results in progressive loss of blood flow, downstream ischemia, and end-organ fibrosis. This forms the pathological basis of transplant arteriosclerosis and other diseases including post-angioplasty re-stenosis. In investigating whether fibrocytes contribute to IH, we previously showed that subpopulations expressing smooth muscle actin and CD31 are recruited to the site of injury and accumulate in the neointima. Expression of tissue factor (TF) by these “CD31+ myofibrocytes” is needed for progressive neointimal expansion, such that TF inhibition limits the neointima to a single layer of cells by day 28 post-injury. The aim of this study was to determine pathophysiological mediators downstream of TF that contribute to myofibrocyte-orchestrated IH. We first show that myofibrocytes make up a significant component of the neointima 28 days following injury. Using a previously defined adoptive transfer model, we then show that CD31+ myofibrocytes get recruited early to the site of injury; this model allows manipulations of the adoptively transferred cells to study how IH develops. Having confirmed that inhibition of TF on adoptively transferred cells prevents IH, we then show that TF, primarily through the generation of thrombin, induces secretion of angiopoietin-2 by myofibrocytes and this directly stimulates proliferation, inhibits apoptosis, and induces CXCL-12 production by neointimal cells, including non-fibrocytes, all of which promote progressive IH in vivo. Prior incubation to inhibit angiopoietin-2 secretion by or block TIE-2 signaling on adoptively transferred fibrocytes inhibits IH. These novel data indicate that angiopoietin-2 production by early recruited myofibrocytes critically influences the development of IH after vascular injury and suggest new therapeutic avenues for exploration.
Highlights
Chronic vascular disease commonly involves intimal hyperplasia (IH) and remodeling of arteries, leading to progressive reduction in blood flow, tissue fibrosis, and eventual organ failure
Many of these cells co-expressed angiopoietin-2 (Figure 1A) but a significant proportion of the angiopoietin-2 expression was in collagen-1-negative, areas, suggesting that angiopoeitin-2 was expressed by cells in the neointima other than myofibrocytes
This data re-affirm that the response to endoluminal injury involves recruitment of myofibrocytes, that these comprise a significant proportion of the neointimal area 28 days post-injury, and that they express angiopoietin-2
Summary
Chronic vascular disease commonly involves intimal hyperplasia (IH) and remodeling of arteries, leading to progressive reduction in blood flow, tissue fibrosis, and eventual organ failure. IH is characterized by progressive accumulation of cells expressing α-smooth muscle actin (SMA) in the intima: the precise origin of these cells has been extensively debated, but several studies in mice [1] and humans [2] suggest that some of these cells can be bone marrow (BM)-derived [3] Working in both wire-induced endoluminal injury and allogeneic aortic transplantation models [4], we previously showed that a BM-derived cell type had a critical influence on the development of IH [5, 6]. We identified that a monocytederived cell type was an early constituent of the neointima We characterized these as CD45+ cells expressing CD31, TIE-2, VEGF-R2, and E-selectin [5], a phenotype consistent with pre vious descriptions of a neointimal cell type [7]. We showed that fibrocytes were mobilized into the peripheral blood of mice post-injury and post-transplantation, accounting for approximately 45% of all CD34+ cells mobilized
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