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Arterial expression of the plasminogen activator system early after cardiac transplantation
M R Garvin1, M Labinaz, K Pels
1Department of Medicine (Cardiology), University of Ottawa Heart Institute, Ont., Canada.
Insights
Altered expression of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in coronary arteries is linked to graft vascular disease after heart transplants. This imbalance may drive thrombosis and cell migration, contributing to arterial narrowing.
Area of Science:
- Cardiovascular Biology
- Transplantation Immunology
- Molecular Medicine
Background:
- Coronary artery narrowing post-transplant, or graft vascular disease (GVD), is a significant complication.
- Tissue thrombolysis and vascular cell migration are implicated in GVD development.
- The plasminogen activation system, involving plasminogen activators and inhibitors, regulates these processes.
Purpose of the Study:
- To investigate the expression patterns of the plasminogen activation system in coronary arteries following cardiac transplantation.
- To understand the role of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the initiation and progression of GVD.
Main Methods:
- In situ hybridization and immunocytochemistry were employed.
- Expression of uPA and PAI-1 in cardiac allograft coronary arteries was compared to healthy controls.
- Analysis focused on vascular cell localization and expression levels.
Main Results:
- Over-expression of both PAI-1 and uPA was observed early after transplantation and persisted up to 27 months.
- This over-expression preceded observable morphological changes indicative of GVD.
- Adventitial microvessels and myofibroblasts showed notable uPA and PAI-1 expression, unlike normal arteries where expression was mainly in endothelial cells.
Conclusions:
- Distinct vascular expression patterns of uPA and PAI-1 exist in transplant coronary arteries compared to normal arteries.
- A local imbalance in the plasminogen system is a potential contributor to GVD.
- Further research is needed to elucidate the precise role of uPA and PAI-1 in arterial thrombosis and cell migration leading to GVD.
Objectives:
Recent studies suggest that alterations in tissue thrombolysis as well as the inward migration of cells may be specific events that contribute to coronary artery narrowing after cardiac transplantation. Plasminogen activators and inhibitors play a central role in governing not only tissue thrombolysis, but also vascular cell migration. The purpose of this study was to examine arterial wall expression of the plasminogen activation system in coronary arteries during graft vascular disease initiation and progression.
Methods:
Using in situ hybridization and immunocytochemistry, the expression patterns of uPA and PAI-1 in coronary arteries from cardiac allografts were compared to those of young individuals without disease.
Results:
Both PAI-1 and uPA were over-expressed early after transplantation and as late as 27 months post grafting. Over-expression of these molecules preceded morphological evidence of graft vascular disease. Of special note was the adventitial expression of uPA and PAI-1 in microvessels and myofibroblasts. In contrast, the expression of uPA and PAI-1 in normal coronary arteries was confined to endothelial cells of the central lumen, as well as low levels of expression in intimal and medial smooth muscle cells.
Conclusions:
Despite morphologic similarities between normal and transplant coronary arteries, differences were noted in the vascular expression pattern of uPA and PAI-1. The exact role of these molecules in graft vascular disease requires further study; however, it is intriguing to consider that a local imbalance in the plasminogen system may contribute to arterial wall thrombosis and/or excessive cell migration and the genesis of complex vascular lesions.