Abstract
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.
Highlights
Gestational Diabetes Mellitus (GDM) is a metabolic disorder defined by high blood glucose levels
Concordantly with previous data, we found that vascular endothelial growth factor (VEGF) protein expression was similar among healthy and GDM Wharton’s Jelly Mesenchymal Stem Cells (WJ-MSC), with comparable protein levels even when cells were exposed to 25 mM D-glucose media for 24–48 h
We evaluated if the secretion of Netrin-1 was altered in GDM Wharton’s Jelly (WJ)-MSC or modulated by glucose levels, for which we measured Netrin-1 levels by ELISA in healthy and GDM WJ-MSC conditioned media (CM) after exposition to 5 mM or 25 mM D-glucose media
Summary
Gestational Diabetes Mellitus (GDM) is a metabolic disorder defined by high blood glucose levels. We showed that the Netrin-1 signalling pathway modulates angiogenesis in the human umbilical cord and that members of the UNC5 family are expressed in primary cultures of HUVEC [13] In both foetal endothelium and stromal cells, we did not detect any expression of DCC [13]. The connective tissue of the umbilical cord, called Wharton’s Jelly (WJ), surrounds the foetal vessels and is thought to prevent compression, torsion and bending [14] This tissue is rich in mesenchymal stem cells (WJ-MSC), which secrete a broad set of molecules that participate in migration, inflammatory response, angiogenesis, tissue repair and coagulation [15]. The present study highlights the participation of a new signalling pathway, Netrin-1/UNC5b, that could be involved in the pathogenesis of GDM, with possible therapeutic relevance
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