Science and Research

LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension

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 beta1-integrin-dependent manner. Furthermore, LRP1 silencing attenuated the expression of fibronectin and collagen I and increased the levels of alpha-smooth muscle actin and myocardin in donor, but not in IPAH, PASMC. In addition, smooth muscle cell (SMC)-specific LRP1 knockout augmented alpha-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.

  • Zucker, M. M.
  • Wujak, L.
  • Gungl, A.
  • Didiasova, M.
  • Kosanovic, D.
  • Petrovic, A.
  • Klepetko, W.
  • Schermuly, R. T.
  • Kwapiszewska, G.
  • Schaefer, L.
  • Wygrecka, M.

Keywords

  • Actins/genetics/metabolism
  • Adult
  • Animals
  • Antibodies, Neutralizing/pharmacology
  • Becaplermin/antagonists & inhibitors/*genetics/metabolism
  • Case-Control Studies
  • Cell Dedifferentiation/*genetics
  • Cell Proliferation/drug effects
  • Collagen Type I/genetics/metabolism
  • Disease Models, Animal
  • Familial Primary Pulmonary Hypertension/chemically
  • induced/*genetics/metabolism/pathology
  • Female
  • Fibronectins/genetics/metabolism
  • Gene Expression Regulation
  • Homeostasis/genetics
  • Humans
  • Integrin beta1/genetics/metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1/antagonists &
  • inhibitors/*genetics/metabolism
  • Male
  • Mice
  • Middle Aged
  • Monocrotaline/administration & dosage
  • Myocytes, Smooth Muscle/drug effects/*metabolism/pathology
  • Nuclear Proteins/genetics/metabolism
  • Pulmonary Artery/drug effects/metabolism/pathology
  • RNA, Small Interfering/genetics/metabolism
  • Rats
  • Receptors, Platelet-Derived Growth Factor/genetics/metabolism
  • Signal Transduction
  • Tissue Culture Techniques
  • Trans-Activators/genetics/metabolism
  • *Cell proliferation
  • *Low density lipoprotein receptor-related protein 1
  • *Pulmonary hypertension
  • *Smooth muscle cell phenotype
  • *beta1-integrin
Publication details
DOI: 10.1016/j.bbadis.2019.03.012
Journal: Biochim Biophys Acta Mol Basis Dis
Pages: 1604-1616 
Number: 6
Work Type: Original
Location: UGMLC
Disease Area: PH
Partner / Member: JLU
Access-Number: 30910704
See publication on PubMed

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