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Open AccessArticle

Downregulation of the Netrin-1 Receptor UNC5b Underlies Increased Placental Angiogenesis in Human Gestational Diabetes Mellitus

Laboratory of Stem Cells and Developmental Biology, Faculty of Sciences, Universidad de Chile, Santiago de Chile 7800024, Chile
Campus Oriente, Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad de Chile, Santiago de Chile 7800024, Chile
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(6), 1408;
Received: 12 December 2018 / Revised: 28 January 2019 / Accepted: 31 January 2019 / Published: 20 March 2019
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
Gestational diabetes mellitus (GDM) is a common metabolic disorder, defined by high blood glucose levels during pregnancy, which affects foetal and post-natal development. However, the cellular and molecular mechanisms of this detrimental condition are still poorly understood. A dysregulation in circulating angiogenic trophic factors, due to a dysfunction of the feto-placental unit, has been proposed to underlie GDM. But even the detailed study of canonical pro-angiogenic factors like vascular endothelial growth factor (VEGF) or basic Fibroblast Growth Factor (bFGF) has not been able to fully explain this detrimental condition during pregnancy. Netrins are non-canonical angiogenic ligands produced by the stroma have shown to be important in placental angiogenesis. In order to address the potential role of Netrin signalling in GDM, we tested the effect of Netrin-1, the most investigated member of the family, produced by Wharton’s Jelly Mesenchymal Stem Cells (WJ-MSC), on Human Umbilical Vein Endothelial Cells (HUVEC) angiogenesis. WJ-MSC and HUVEC primary cell cultures from either healthy or GDM pregnancies were exposed to physiological (5 mM) or high (25 mM) d-glucose. Our results reveal that Netrin-1 is secreted by WJ-MSC from healthy and GDM and both expression and secretion of the ligand do not change with distinct experimental glucose conditions. Noteworthy, the expression of its anti-angiogenic receptor UNC5b is reduced in GDM HUVEC compared with its expression in healthy HUVEC, accounting for an increased Netrin-1 signalling in these cells. Consistently, in healthy HUVEC, UNC5b overexpression induces cell retraction of the sprouting phenotype. View Full-Text
Keywords: GDM; UNC5b; angiogenesis; Netrin-1; HUVEC; WJ-MSC GDM; UNC5b; angiogenesis; Netrin-1; HUVEC; WJ-MSC
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Prieto, C.P.; Casas, B.S.; Falcón, P.; Villanueva, A.; Lois, P.; Lattus, J.; Palma, V. Downregulation of the Netrin-1 Receptor UNC5b Underlies Increased Placental Angiogenesis in Human Gestational Diabetes Mellitus. Int. J. Mol. Sci. 2019, 20, 1408.

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