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

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.

Anti-Inflammatory Role of Netrin-4 in Diabetic Retinopathy

“…Alternatively, a study on cerebral ischemia demonstrated that after stroke, NTN4 is upregulated in astrocytes and blood vessels of the ischemic core, and DCC but not UNC5B is upregulated in neuronal processes [ 18 ]. Another published study described UNC5B to be downregulated using human umbilical vascular endothelial cells in an angiogenesis model for gestational diabetes in the placenta [ 19 ]. We believe this discrepancy could be influenced, firstly, by the in vitro approach of the experiments, and that the tissue studied by Prieto and colleagues does not belong to the central nervous system and lacks the NTN4 neuronal and glial contribution [ 18 , 20 ].…”

Endothelial Dysfunction in Pregnancy Complications

“…Prieto et al reported that Netrin-1 and its receptors might regulate the increased placental angiogenesis observed in GDM. They found the decreased expression of anti-angiogenic Unc-5 Netrin Receptor B in HUVECs obtained from patients with GDM [ 174 ]. In turn, Peng et al discovered increased miR-137 plasma levels in women with GDM and HUVECs exposed to hyperglycemia.…”

Does the Act of Copulation per se, without Considering Seminal Deposition, Change the Expression of Genes in the Porcine Female Genital Tract?

“…Furthermore, Netrin 4 (NTN4), which was found to be upregulated in the Cvx after mating, is a member of the heterogeneous family of laminin-related proteins that also participates in the regulation of angiogenesis in several tissues including embryos [61,62]. In addition, Netrins functions include essential contributions to regulating cell-cell and cell-matrix adhesion, tissue morphogenesis and the maintenance of appropriate cell-cell interactions [63] all of which are implicated in gamete interaction and early embryo development [64,65]. All these findings pose the idea that, although fertility after AI is comparable to that achieved by natural mating, the latter appears to induce physiological mechanisms of endometrial receptiveness more efficiently, not necessarily through semen influence, but even initiated by copulation stimulus.…”