TRP X8 Endothelial-to-mesenchymal transition

Funding period: 01.09.2015 – 31.08.2018

Publications

• Schütz E, Bochenek ML, Riehl DR, Bosmann M, Münzel T, Konstantinides S, Schäfer K. Absence of transforming growth factor beta 1 in murine platelets reduces neointima formation without affecting arterial thrombosis. Thromb Haemost 2017;117(9):1782-1797.

Project Summary

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension. Clinical as well as experimental evidence suggests that CTEPH represents a misguided, chronic fibrotic response of the lung to unresolved pulmonary embolism or in situ thrombosis; however, the exact pathomechanisms underlying the development of thrombofibrotic pulmonary artery stenosis are largely unknown. It has been suggested that hyperproliferative endothelial cells, activated mesenchymal cells and endothelial-to-mesenchymal transition (EndMT) may be causally involved in CTEPH. Interestingly, EndMT can be induced by transforming growth factor (TGF)-β, a major constituent of platelet α-granules, suggesting that platelet activation may contribute to the phenotypic conversion of endothelial cells into myofibroblasts. Our preliminary findings suggest that pulmonary endothelial cells express high levels of mediators involved in TGFβ signaling, such as Smad1, Smad7 or Smad9. In the present project, we propose to examine the role of platelets and platelet-derived factors, in particular TGFβ released from activated platelets, during the chronic tissue remodeling response of the lung to unresolved thrombotic material and whether they might play a role in the phenotypic conversion of pulmonary endothelial cells into extracellular matrix-producing myofibroblasts and pulmonary scar formation. Findings in human pulmonary artery endothelial cells as well as in genetically modified mice (e.g. EndMT reporter and platelet-specific TGFβ knockout mice) after induction of venous thrombosis by inferior V. cava ligation will be verified by the analysis of human material (e.g. primary lung endothelial cells, circulating endothelial cells) obtained from healthy individuals and patients with the disease.

Principle Investigator

Staff