Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Crnkovic, S; Rittchen, S; Jandl, K; Gindlhuber, J; Zabini, D; Mutgan, AC; Valzano, F; Boehm, PM; Hoetzenecker, K; Toller, W; Veith, C; Heinemann, A; Schermuly, RT; Olschewski, A; Marsh, LM; Kwapiszewska, G.
Divergent Roles of Ephrin-B2/EphB4 Guidance System in Pulmonary Hypertension.
Hypertension. 2023; 80(2):e17-e28
Doi: 10.1161/HYPERTENSIONAHA.122.19479
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- Crnkovic Slaven
- Kwapiszewska-Marsh Grazyna
- Rittchen Sonja
- Co-Autor*innen der Med Uni Graz
- Gindlhuber Jürgen
- Heinemann Akos
- Jandl Katharina
- Marsh Leigh
- Mutgan Redolfi Ayse Ceren
- Olschewski Andrea
- Toller Wolfgang
- Valzano Francesco
- Zabini Diana
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- Abstract:
- BACKGROUND: Smooth muscle cell (SMC) expansion is one key morphological hallmark of pathologically altered vasculature and a characteristic feature of pulmonary vascular remodeling in pulmonary hypertension. Normal embryonal vessel maturation requires successful coverage of endothelial tubes with SMC, which is dependent on ephrin-B2 and EphB4 ligand-receptor guidance system. In this study, we investigated the potential role of ephrin-B2 and EphB4 on neomuscularization in adult pulmonary vascular disease. METHODS AND RESULTS: Ephrin-B2 and EphB4 expression is preserved in smooth muscle and endothelial cells of remodeled pulmonary arteries. Chronic hypoxia-induced pulmonary hypertension was not ameliorated in mice with SMC-specific conditional ephrin-B2 knockout. In mice with global inducible ephrin-B2 knockout, pulmonary vascular remodeling and right ventricular hypertrophy upon chronic hypoxia exposure were significantly diminished compared to hypoxic controls, while right ventricular systolic pressure was unaffected. In contrast, EphB4 receptor kinase activity inhibition reduced right ventricular systolic pressure in hypoxia-induced pulmonary hypertension without affecting pulmonary vascular remodeling. Genetic deletion of ephrin-B2 in murine pulmonary artery SMC, and pharmacological inhibition of EphB4 in human pulmonary artery smooth muscle cells, blunted mitogen-induced cell proliferation. Loss of EphB4 signaling additionally reduced RhoA expression and weakened the interaction between human pulmonary artery smooth muscle cells and endothelial cells in a three-dimensional coculture model. CONCLUSIONS: In sum, pulmonary vascular remodeling was dependent on ephrin-B2-induced Eph receptor (erythropoietin-producing hepatocellular carcinoma receptor) forward signaling in SMC, while EphB4 receptor activity was necessary for RhoA expression in SMC, interaction with endothelial cells and vasoconstrictive components of pulmonary hypertension.
- Find related publications in this database (Keywords)
- Ephrin-B2
- EphB4
- pulmonary hypertension
- pulmonary vascular remodeling
- smooth muscle cells