Fetal Insulin and IGF-II Contribute to Gestational Diabetes Mellitus (GDM)-Associated Up-Regulation of Membrane-Type Matrix Metalloproteinase 1 (MT1-MMP) in the Human Feto-Placental Endothelium

Hiden, Ursula; Lassance, Luciana; Tabrizi, N. Ghaffari; Miedl, Heidi; Tam‐Amersdorfer, Carmen; Cetin, Irene; Lang, Uwe; Desoyé, Gernot

doi:10.1210/jc.2012-1212

Cited by 52 publications

(32 citation statements)

References 41 publications

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“…Also the pleiotropic functions of HBCs are still somewhat enigmatic (40); it has been suggested by various studies that one function of HBCs is to regulate placental vasculo- and angiogenesis (23–25). In GDM, often placental hypervascularization is observed (62, 63), resulting in excessive nutrient transport to the fetus and fetal macrosomia. It would have been tempting to relate the HBC polarization state to this hypervascularization and perinatal outcome; however, it is M2 but not M1 macrophages that have been assigned a pro-angiogenic phenotype (64).…”

Section: Discussionmentioning

confidence: 99%

Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus

et al. 2017

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BackgroundHofbauer cells (HBCs) are macrophages of the feto-placental unit. Despite the general view that these cells have an anti-inflammatory M2 phenotype, recent studies have claimed that pregnancy pathologies—e.g., gestational diabetes mellitus (GDM)—cause a switch from an M2 to an M1 pro-inflammatory phenotype in HBCs. The pilot-study presented here challenges this claim, showing that HBCs maintain anti-inflammatory properties in spite of the hyperglycemic, low-grade inflammatory environment of GDM.MethodsHBCs were isolated from placentae of healthy women (N = 5) and women with GDM (N = 6) diagnosed in the second trimester. FACS was used to measure surface markers associated with either M1 or M2 phenotype on the cells. In addition, placental tissue sections were subjected to immune histochemical imaging to assess the phenotype within the tissue context. Supernatant from control and GDM HBCs was collected at defined time points and used in a multiplex ELISA-on-beads approach to assess secretion of cytokines, chemokines, and growth factors. The effect of HBC cell culture supernatant on placental endothelial activation was investigated.ResultsFACS and immune staining showed that, indeed, M2 markers, such as CD206 and CD209, are increased in HBCs isolated from GDM placentae. Also, the M1 marker CD86 was increased, but only by trend. Secretion of numerous cytokines, chemokines and growth factors was not changed; pro-inflammatory interleukin (IL)-1β and IL-6 release form GDM HBC was increased but not significant. Exposure to GDM HBC supernatant did not induce cell adhesion molecules (VCAM-1, selectins, vascular endothelial-cadherin) in placental endothelial cells compared to supernatant from control HBCs, an induction of intracellular adhesion molecule 1 was observed however.ConclusionOur study—although performed in a small set of patients—shows that placental macrophages maintain their anti-inflammatory, tissue remodeling M2 phenotype even in pregnancies affected by gestational diabetes. This consistent phenotype might be important for propagation of maternal tolerance toward the fetus and for protection of the fetus from a low-grade inflammatory environment.

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Section: Discussionmentioning

confidence: 99%

Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus

et al. 2017

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“…Insulin-dependent first trimester trophoblast cell proliferation was shown to be dependent on the insulin-growth signaling pathway as MAPK inhibitors prevented mitogenesis (Boileau et al, 2001). Regulation of trophoblast invasion by insulin is mediated, at least in part, by membrane type metalloproteinase (Hiden, Glitzner, Ivanisevic et al, 2008, Hiden, Lassance, Tabrizi et al, 2012), which in cancer cell lines have been demonstrated to be dependent on insulin-metabolic pathway involving PI3K/Akt signaling. Therefore placental insulin-resistance mediated by IL-1β or other pro-inflammatory cytokines early in gestation may impact upon placental development and consequently impair placental function.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts

Aye¹,

Jansson²,

Powell³

2013

Molecular and Cellular Endocrinology

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Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1β (10 pg/ml) for 24 hours. IL-1β increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor β expression. Furthermore, IL-1β inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1β alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth.

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“…Fetal cord insulin is positively associated with capillary surface area of the placenta at the end of gestation [5, 128]. In isolated fetoplacental endothelial cells insulin binding to its receptors stimulates several pathways that promote angiogenesis, including the activation of the small GTPase Rac1, eNOS, and expression of the matrix metalloproteinase MT1-MMP [129, 130]. …”

Section: Effect Of Maternal Diabetes On Proangiogenic Factors In Pmentioning

confidence: 99%

Glucose, Insulin, and Oxygen Interplay in Placental Hypervascularisation in Diabetes Mellitus

Cvitic

Desoyé

Hiden

2014

BioMed Research International

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The placental vasculature rapidly expands during the course of pregnancy in order to sustain the growing needs of the fetus. Angiogenesis and vascular growth are stimulated and regulated by a variety of growth factors expressed in the placenta or present in the fetal circulation. Like in tumors, hypoxia is a major regulator of angiogenesis because of its ability to stimulate expression of various proangiogenic factors. Chronic fetal hypoxia is often found in pregnancies complicated by maternal diabetes as a result of fetal hyperglycaemia and hyperinsulinemia. Both are associated with altered levels of hormones, growth factors, and proinflammatory cytokines, which may act in a proangiogenic manner and, hence, affect placental angiogenesis and vascular development. Indeed, the placenta in diabetes is characterized by hypervascularisation, demonstrating high placental plasticity in response to diabetic metabolic derangements. This review describes the major regulators of placental angiogenesis and how the diabetic environment in utero alters their expression. In the light of hypervascularized diabetic placenta, the focus was placed on proangiogenic factors.

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Fetal Insulin and IGF-II Contribute to Gestational Diabetes Mellitus (GDM)-Associated Up-Regulation of Membrane-Type Matrix Metalloproteinase 1 (MT1-MMP) in the Human Feto-Placental Endothelium

Abstract: GDM up-regulates MT1-MMP in the feto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature.

Cited by 52 publications

References 41 publications

Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus

Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus

Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts

Glucose, Insulin, and Oxygen Interplay in Placental Hypervascularisation in Diabetes Mellitus

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