Nandi Pinki, Siddiqui Mohammad Fyyaz, Lala Peeyush K
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.
Am J Reprod Immunol. 2016 Mar;75(3):351-60. doi: 10.1111/aji.12449. Epub 2015 Nov 11.
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.
核心蛋白聚糖（DCN）是一种富含亮氨酸、能结合转化生长因子-β（TGF-β）的蛋白聚糖，由包括软骨细胞、真皮成纤维细胞和子宫蜕膜细胞在内的间充质细胞产生。它具有多种生理功能，包括胶原纤维形成、肌生成、血管生成抑制以及抑制胎盘侵袭性。我们发现，蜕膜来源的DCN以不依赖TGF-β的方式抑制人胎盘绒毛外滋养层（EVT）细胞的增殖、迁移和侵袭。这些功能是由DCN与多种酪氨酸激酶受体（TKR）结合介导的，这些受体包括表皮生长因子受体（EGFR）、胰岛素样生长因子受体1（IGFR1）和血管内皮生长因子受体2（VEGFR2）。DCN通过抑制P38丝裂原活化蛋白激酶（P38MAPK）和细胞外信号调节激酶1/2（ERK1/2）信号通路，阻断VEGFR-2依赖的EVT细胞迁移和血管内分化。我们确定DCN蛋白中与VEGFR2的高亲和力结合位点位于结构域III富含亮氨酸重复序列（LRR）5区域的12个氨基酸（LGTNPLKSSGIE）跨度范围内。DCN在此位点的单个氨基酸突变（K替换为A）消除了VEGFR-2依赖的DCN作用。此外，通过原位杂交检测发现，子痫前期（PE）母亲胎盘的蜕膜细胞中DCN mRNA表达选择性上调，而绒毛膜绒毛间充质细胞中的表达水平保持不变。PE胎盘与对照胎盘之间的这种差异在所有孕周均存在，表明DCN在PE发病机制中的作用。我们推测血液中DCN水平升高可能是PE的一个候选生物标志物。
