LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension |
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| Authors: | Marius M. Zucker Lukasz Wujak Anna Gungl Miroslava Didiasova Djuro Kosanovic Aleksandar Petrovic Walter Klepetko Ralph T. Schermuly Grazyna Kwapiszewska Liliana Schaefer Malgorzata Wygrecka |
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| Affiliation: | 1. Department of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany;2. Ludwig Boltzmann Institute for Lung Vascular Research, Medical University Graz, Graz, Austria;3. Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany;4. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;5. Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria;6. Goethe University, School of Medicine, Frankfurt am Main, Germany |
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| Abstract: | Pulmonary hypertension (PH) is characterized by a thickening of the distal pulmonary arteries caused by medial hypertrophy, intimal proliferation and vascular fibrosis. Low density lipoprotein receptor-related protein 1 (LRP1) maintains vascular homeostasis by mediating endocytosis of numerous ligands and by initiating and regulating signaling pathways.Here, we demonstrate the increased levels of LRP1 protein in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline-treated rats. Platelet-derived growth factor (PDGF)-BB upregulated LRP1 expression in pulmonary artery smooth muscle cells (PASMC). This effect was reversed by the PDGF-BB neutralizing antibody or the PDGF receptor antagonist. Depletion of LRP1 decreased proliferation of donor and IPAH PASMC in a β1-integrin-dependent manner. Furthermore, LRP1 silencing attenuated the expression of fibronectin and collagen I and increased the levels of α-smooth muscle actin and myocardin in donor, but not in IPAH, PASMC. In addition, smooth muscle cell (SMC)-specific LRP1 knockout augmented α-SMA expression in pulmonary vessels and reduced SMC proliferation in 3D ex vivo murine lung tissue cultures.In conclusion, our results indicate that LRP1 promotes the dedifferentiation of PASMC from a contractile to a synthetic phenotype thus suggesting its contribution to vascular remodeling in PH. |
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| Keywords: | Corresponding author at: Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany. α-SMA α-smooth muscle actin EC endothelial cell ECM extracellular matrix FN fibronectin HOX hypoxia IPAH idiopathic pulmonary arterial hypertension LRP1 low density lipoprotein receptor-related protein 1 MCT monocrotaline MMP matrix metalloprotease NOX normoxia PASMC pulmonary artery smooth muscle cell PDGF platelet-derived growth factor PDGFR PDGF receptor PH pulmonary hypertension SMC smooth muscle cell Pulmonary hypertension Low density lipoprotein receptor-related protein 1 β1-integrin Smooth muscle cell phenotype Cell proliferation |
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