Related Experiment Video
Updated: May 30, 2026
Mouse Models for Graft Arteriosclerosis
Published on: May 14, 2013
Intimal fibrosis in human cardiac allograft vasculopathy
Manon Huibers1, Nicolaas De Jonge, Joyce Van Kuik
1Department of Pathology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. m.m.h.huibers@umcutrecht.nl
Insights
Human Cardiac Allograft Vasculopathy (CAV) involves coronary artery fibrosis. T-cells producing interferon gamma and transforming growth factor beta drive this process by increasing connective tissue growth factor in CAV vessels.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Fibrosis Mechanisms
Background:
- Human Cardiac Allograft Vasculopathy (CAV) is a primary complication following heart transplantation.
- CAV is characterized by progressive narrowing of donor coronary arteries due to intimal expansion and fibrosis.
Purpose of the Study:
- To investigate the specific cellular and molecular factors contributing to the fibrotic process in CAV.
- To identify key cells and signaling pathways involved in CAV pathogenesis.
Main Methods:
- Analysis of coronary arteries from heart transplant recipients with CAV and controls.
- Laser microdissection of arterial layers for quantitative real-time PCR.
- Confirmation of gene expression via immunohistochemistry and in situ hybridization.
Main Results:
- Pro-fibrotic gene expression, particularly connective tissue growth factor, was highest in the neo-intima of CAV vessels.
- Lymphocytes producing interferon gamma and transforming growth factor beta were detected exclusively in CAV vessels.
- Anti-fibrotic bone morphogenic protein 4 was expressed by stromal cells, while M2 macrophages showed no pro-fibrotic activity.
Conclusions:
- T-cells secreting both interferon gamma and transforming growth factor beta are implicated in CAV fibrosis.
- These T-cells may promote CAV by upregulating connective tissue growth factor in the coronary arteries.
Abstract:
Human Cardiac Allograft Vasculopathy (CAV) is one of the major complications for patients after heart transplantation. It is characterized by a concentric luminal narrowing due to (neo) intimal expansion in the coronary arteries of donor hearts after heart transplantation. In this process fibrosis plays an important role. Aim of this study is to analyze the factors and cells involved in this fibrotic process. Coronary arteries from five heart transplantation patients and three controls were obtained at autopsy. Quantitative real-time PCR was performed on mRNA obtained from various arterial layers isolated by laser micro dissection. Positive gene expression was confirmed by immunohistochemistry and/or in situ hybridisation. The strongest mRNA expression of fibrotic factors (predominantly pro-fibrotic) was found in the neo-intima. Especially, connective tissue growth factor expression was higher in the CAV vessels than in the controls. The lymphocyte activity of interferon gamma was only detected in CAV vessels. Furthermore as shown by in situ hybridisation, the lymphocytes producing interferon gamma also expressed transforming growth factor beta. Anti-fibrotic factors, such as bone morphogenic protein 4, were only expressed in CD3(-)/CD68(-) stromal cells. Macrophages present in the CAV and control vessels showed to be of the M2 type and did not produce any fibrotic factor(s). In conclusion, T-cells producing both interferon gamma and transforming growth factor beta, may play an important role in the fibrotic process in CAV vessels by upregulation of connective tissue growth factor production.
