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Restraint of Trophoblast Invasion of the Uterus by Decorin: Role in Pre‐eclampsia
Author(s) -
Nandi Pinki,
Siddiqui Mohammad Fyyaz,
Lala Peeyush K
Publication year - 2016
Publication title -
american journal of reproductive immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.071
H-Index - 97
eISSN - 1600-0897
pISSN - 1046-7408
DOI - 10.1111/aji.12449
Subject(s) - decorin , trophoblast , decidua , biology , microbiology and biotechnology , receptor , in situ hybridization , endocrinology , placenta , medicine , proteoglycan , fetus , messenger rna , biochemistry , extracellular matrix , genetics , gene , pregnancy
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 , IGFR 1, and VEGFR 2. DCN blocked VEGFR ‐2 dependent EVT cell migration and endovascular differentiation by inhibiting P38 MAPK and ERK 1/2 pathways.We identified the avid VEGFR 2 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 .