Activation of Adventitial Fibroblasts in the Early Stage of the Aortic Transplant Vasculopathy in Rat

Ji, Jian; Xu, Fang; Li, Li; Chen, Rong; Wang, Jianli; Hu, Wei Cheng

doi:10.1097/tp.0b013e3181d05aa7

Cited by 23 publications

(25 citation statements)

References 44 publications

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“…The vascular adventitia has been implied as a source of cells that contribute to intimal hyperplasia [41,43,58] and migrate in the vessel wall in order to localize in vascular lesions [59]. Here, we investigated whether cells derived from infected adventitia migrated to the intima and if migration of adventitial cells was altered by RCMV.…”

Section: Discussionmentioning

confidence: 99%

RCMV increases intimal hyperplasia by inducing inflammation, MCP-1 expression and recruitment of adventitial cells to intima

et al. 2010

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BackgroundCytomegalovirus (CMV) infection has been associated with accelerated transplant vasculopathy. In this study, we assessed the effects of acute rat CMV (RCMV) infection on vessel remodeling in transplant vasculopathy, focusing on allograft morphology, inflammation and contribution of adventitial cells to intimal hyperplasia.MethodsInfrarenal aorta was locally infected with RCMV and transplanted from female F344 rats to male Lewis rats. Graft samples were collected 2 and 8 weeks after transplantation and analyzed for intimal hyperplasia, collagen degradation and inflammation. Transplantation of aorta followed by transplantation of RCMV infected and labeled isogenic adventitia were performed to study migration of adventitial cells towards the intima.ResultsIntimal hyperplasia was increased threefold in infected allografts. RCMV induced apoptosis in the media, expression of matrix metalloproteinase 2, and decreased collagen deposits. Macrophage infiltration was increased in the infected allografts and resulted in increased production of MCP-1. RCMV-infected macrophages were observed in the adventitia and intima. Cells derived from infected adventitia migrated towards the intima of the allograft.ConclusionsRCMV enhances infiltration of macrophages to the allografts, and thereby increases MCP-1 production and inflammation, followed by recruitment of adventitial cells to the intima and accelerated intimal hyperplasia.

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Section: Discussionmentioning

confidence: 99%

RCMV increases intimal hyperplasia by inducing inflammation, MCP-1 expression and recruitment of adventitial cells to intima

et al. 2010

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“…Sprague‐Dawley rats were used as donors and syngeneic recipients, and Wistar rats served as allogeneic recipients, as described by Ji et al (26). Abdominal aortic transplantation was performed using a modified technique described initially by Mennander et al (27).…”

Section: Methodsmentioning

confidence: 99%

Vascular Smooth Muscle Cell Apoptosis Promotes Transplant Arteriosclerosis Through Inducing the Production of SDF-1α

Liu

et al. 2012

American Journal of Transplantation

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Transplant arteriosclerosis is a leading cause of late allograft loss. Medial smooth muscle cell (SMC) apoptosis is considered to be an important event in transplant arteriosclerosis. However, the precise contribution of medial SMC apoptosis to transplant arteriosclerosis and the underlying mechanisms remain unclear. We transferred wild‐type p53 to induce apoptosis of cultured SMCs. We found that apoptosis induces the production of SDF‐1α from apoptotic and neighboring viable cells, resulting in increased SDF‐1α in the culture media. Conditioned media from Ltv‐p53‐transferred SMCs activated PI3K/Akt/mTOR and MAPK/Erk signaling in a SDF‐1α‐dependent manner and thereby promoted mesenchymal stem cell (MSC) migration and proliferation. In a rat aorta transplantation model, lentivirus‐mediated BclxL transfer selectively inhibits medial SMC apoptosis in aortic allografts, resulting in a remarkable decrease of SDF‐1α both in allograft media and in blood plasma, associated with diminished recruitment of CD90+CD105+ double‐positive cells and impaired neointimal formation. Systemic administration of rapamycin or PD98059 also attenuated MSC recruitment and neointimal formation in the aortic allografts. These results suggest that medial SMC apoptosis is critical for the development of transplant arteriosclerosis through inducing SDF‐1α production and that MSC recruitment represents a major component of vascular remodeling, constituting a relevant target and mechanism for therapeutic interventions.

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“…Male F344 and Lewis inbred rats (weighing 220–270 g) were purchased from Charles River Laboratories (Beijing, China). Allograft aortic transplantation was performed as described previously using a cuff-based technique [14, 15]. Briefly, thoracic aortas from F344 rats were removed and inserted into the abdominal region of recipient Lewis rats between the levels of renal artery and iliac bifurcation.…”

Section: Methodsmentioning

confidence: 99%

“…Paraffin-embedded tissue sections were cut and stained with hematoxylin and eosin. Morphometric measurements of the average thickness of the intimal, medial and adventitial layers were carried out as described in our previous studies [14, 15]. …”

Section: Methodsmentioning

confidence: 99%

“…This early adventitial activation is characterized by cellularization and thickening of the layer, increased proliferation and trans-differentiation of fibroblasts, expression of multiple pro-inflammatory molecules, and increased expression of NADPH oxidase [14, 15]. Interestingly, we have identified that CD68 + macrophages, but not CD3 + T lymphocytes, are the predominant type of leukocytes infiltrating the activated adventitia [14].…”

Section: Introductionmentioning

confidence: 99%

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Macrophage-stimulated microRNA expression in mural cells promotes transplantation-induced neointima formation

et al. 2017

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In this study, we tested the possibility that macrophages might contribute to neointima formation by stimulating microRNA expressions in mural cells. Thoracic aortas from F344 rats were transplanted into recipient Lewis rats. Clodronate liposome was used for in vivo macrophage depletion. Using miR-21 as a prototypic example of vascular enriched microRNA, we showed that macrophage depletion reduced the expression level of miR-21, which was upregulated in the allograft. This effect of macrophage depletion was accompanied by attenuations in neointimal hyperplasia and transplantation-induced vascular inflammation. Using in vitro assays, we identified that macrophages might stimulate miR-21 expression in smooth muscle cells and adventitial fibroblasts via the release of tumor necrosis factor-α. We also showed that silencing of miR-21 suppressed tumor necrosis factor-induced proliferation, migration, and inflammatory responses in mural cells. Our results suggest that macrophage may promote transplantation-induced neointima formation by stimulating miR-21 expression in vascular mural cells, which promotes mural cell proliferation, migration and/or inflammation. Moreover, we have established that tumor necrosis factor-α has a major role in mediating this paracrine process.

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Activation of Adventitial Fibroblasts in the Early Stage of the Aortic Transplant Vasculopathy in Rat

Abstract: These results demonstrated that adventitial fibroblasts are activated and can produce cytokines and chemokines before the neointimal hyperplasia. They may exert a potential effect on the development of neointimal hyperplasia in TV.

Cited by 23 publications

References 44 publications

RCMV increases intimal hyperplasia by inducing inflammation, MCP-1 expression and recruitment of adventitial cells to intima

RCMV increases intimal hyperplasia by inducing inflammation, MCP-1 expression and recruitment of adventitial cells to intima

Vascular Smooth Muscle Cell Apoptosis Promotes Transplant Arteriosclerosis Through Inducing the Production of SDF-1α

Macrophage-stimulated microRNA expression in mural cells promotes transplantation-induced neointima formation

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