title: Restraint of Trophoblast Invasion of the Uterus by Decorin: Role in Pre-eclampsia.
abstract: Decorin (DCN) is a leucine-rich, TGF-β binding proteoglycan produced by mesenchymal cells including chondrocytes, dermal fibroblasts, and uterine decidual cells. It exerts multiple physiological functions including collagen fibrillogenesis, myogenesis, angiostasis, and restraining placental invasiveness. We discovered that decidua-derived DCN restrains proliferation, migration, and invasion of extravillous trophoblast (EVT) cells of the human placenta in a TGF-β-independent manner. These functions were differentially mediated by binding of DCN to multiple tyrosine kinase receptors (TKR) including EGFR, IGFR1, and VEGFR2. DCN blocked VEGFR-2 dependent EVT cell migration and endovascular differentiation by inhibiting P38MAPK and ERK1/2 pathways.We identified the avid VEGFR2 binding site in DCN protein as a 12 amino acids (LGTNPLKSSGIE) span in the Leucine-rich-repeat (LRR) 5 region of domain III. A single amino acid mutation (substitution of K to A) of DCN at this site abrogated VEGFR-2- dependent DCN actions. Also, DCN mRNA expression, measured with in situ hybridization, was selectively upregulated in decidual cells in placentas from mothers suffering from pre-eclampsia (PE), whereas the expression levels remained unchanged in chorionic villus mesenchymal cells. This difference between PE and control placentas was present at all gestational ages, indicating the pathogenic role of DCN in PE. We hypothesize that increased blood DCN levels could be a candidate biomarker for PE.
authors.affiliation: Departments of Anatomy and Cell biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.
authors.forename: Pinki
authors.initials: P
authors.lastname: Nandi
authors.affiliation: Departments of Anatomy and Cell biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.
authors.forename: Mohammad Fyyaz
authors.initials: MF
authors.lastname: Siddiqui
authors.affiliation: Departments of Anatomy and Cell biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.|Department of Oncology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.|Children's Health Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.
authors.forename: Peeyush K
authors.initials: PK
authors.lastname: Lala
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D003656:Decidua / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058575:Decorin / Q000097:blood / Q000276:immunology*; D010064:Embryo Implantation / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D011225:Pre-Eclampsia / Q000097:blood / Q000276:immunology*; D011247:Pregnancy; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D014327:Trophoblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; C546878:DCN protein, human; D058575:Decorin; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Angiogenesis; decorin; intrauterine growth restriction; pre-eclampsia; trophoblast invasion; uterine arterial remodeling