Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zucker, MM; Wujak, L; Gungl, A; Didiasova, M; Kosanovic, D; Petrovic, A; Klepetko, W; Schermuly, RT; Kwapiszewska, G; Schaefer, L; Wygrecka, M.
LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension.
Biochim Biophys Acta Mol Basis Dis. 2019; 1865(6):1604-1616
Doi: 10.1016/j.bbadis.2019.03.012
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- Co-Autor*innen der Med Uni Graz
- Birnhuber Anna
- Kwapiszewska-Marsh Grazyna
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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. Copyright © 2019 Elsevier B.V. All rights reserved.
- Find related publications in this database (Keywords)
- Pulmonary hypertension
- Low density lipoprotein receptor-related protein 1
- beta 1-integrin
- Smooth muscle cell phenotype
- Cell proliferation