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Updated: Oct 2, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis
Roope K Sihvola1, Ville P Pulkkinen, Petri K Koskinen
1Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland. Roope.Sihvola@Helsinki.Fi
Insights
Endothelin-1 (ET-1) signaling promotes smooth muscle cell proliferation and migration in cardiac allograft arteriosclerosis. Blocking ET-1 receptors with Bosentan reduced lesions and platelet-derived growth factor receptor beta (PDGF-Rbeta) expression, suggesting a key therapeutic pathway.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Cell Biology
Background:
- Cardiac allograft arteriosclerosis, a form of chronic rejection, is associated with endothelin-1 (ET-1) and platelet-derived growth factor (PDGF).
- Previous research indicated independent roles for ET-1 and PDGF in developing cardiac allograft arteriosclerosis.
Purpose of the Study:
- To investigate the crosstalk between ET-1 and PDGF in smooth muscle cell (SMC) proliferation within the rat cardiac allograft model.
- To elucidate the therapeutic potential of targeting ET-1 signaling in chronic rejection.
Main Methods:
- Heterotopic rat heart transplantation models (acute and chronic rejection).
- In vitro studies quantifying SMC proliferation, migration, and mRNA expression of ET-1 and PDGF ligands/receptors.
- Treatment with Bosentan (ET-1 receptor antagonist) and CGP 53716 (PDGF receptor inhibitor).
Main Results:
- ET-1 and its receptors (ET(A), ET(B)) were strongly correlated with intimal thickening in chronic allografts.
- Bosentan treatment significantly reduced arteriosclerotic lesions and ET(A)/ET(B) mRNA expression, alongside decreased PDGF-Rbeta mRNA.
- CGP 53716 did not affect ET-1 or its receptor mRNA levels.
- ET-1 stimulation in SMC cultures upregulated PDGF receptor expression and enhanced PDGF-BB-mediated SMC proliferation and migration.
Conclusions:
- The ET-1/PDGF-Rbeta/PDGF-BB axis plays a significant role in SMC migration and proliferation in cardiac allograft arteriosclerosis.
- Blocking ET-1 receptor signaling offers a promising therapeutic strategy for mitigating chronic rejection by targeting this axis.
Objectives:
In this study, we investigated the crosstalk of endothelin-1 (ET-1) and platelet-derived growth factor (PDGF) in coronary artery smooth muscle cell (SMC) proliferation in the rat cardiac allograft model.
Background:
Previous studies have suggested an independent role of ET-1 and PDGF in the development of cardiac allograft arteriosclerosis (i.e., chronic rejection).
Methods:
Heterotopic heart transplantations were performed from Dark Agouti to Wistar Furth rats. Grafts were harvested after five days in an acute rejection model and after 60 days in a chronic rejection model. In the in vitro part of the study, SMC proliferation and migration were quantitated, as well as messenger ribonucleic acid (mRNA) levels of ET-1 and PDGF ligands and receptors after growth factor stimulation.
Results:
Acute rejection induced both ET-1 receptors in the arterial wall. On linear regression analysis of chronically rejecting cardiac allografts, a strong correlation between intimal thickening and immunoreactivity of ET-1 and ET receptors A and B (ET(A) and ET(B)) in the arterial walls was observed. Treatment with Bosentan, a mixed ET-1 receptor antagonist, significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac allografts, as well as total intragraft ET(A) and ET(B) mRNA expression and intimal cell ET-1 and receptor immunoreactivity. This was associated with significantly reduced intragraft PDGF beta-receptor (PDGF-Rbeta) mRNA expression. In contrast, CGP 53716, a protein tyrosine kinase inhibitor selective for the PDGF receptor, did not reduce intragraft ET-1, ET(A) or ET(B) mRNA expression. In rat coronary artery SMC cultures, ET-1 stimulation significantly upregulated PDGF-Ralpha and -Rbeta mRNA expression and augmented PDGF-BB-mediated SMC proliferation as well as PDGF-AB- and PDGF-BB-mediated SMC migration.
Conclusions:
Our results suggest that the ET-1/PDGF-Rbeta/PDGF-BB axis may operate in SMC migration and proliferation in cardiac allograft arteriosclerosis, thus explaining the marked beneficial effects of blocking the signaling downstream of ET-1 receptors.
