Vasoactive Intestinal Peptide induces glucose and neutral amino acid uptake through mTOR signalling in human cytotrophoblast cells

Abstract

The transport of nutrients across the placenta involves trophoblast cell specific transporters modulated through the mammalian target of rapamycin (mTOR). The vasoactive intestinal peptide (VIP) has embryotrophic effects in mice and regulates human cytotrophoblast cell migration and invasion. Here we explored the effect of VIP on glucose and System A amino acid uptake by human trophoblast-derived cells (Swan 71 and BeWo cell lines). VIP activated D-glucose specific uptake in single cytotrophoblast cells in a concentration-dependent manner through PKA, MAPK, PI3K and mTOR signalling pathways. Glucose uptake was reduced in VIP-knocked down cytotrophoblast cells. Also, VIP stimulated System A amino acid uptake and the expression of GLUT1 glucose transporter and SNAT1 neutral amino acid transporter. VIP increased mTOR expression and mTOR/S6 phosphorylation whereas VIP silencing reduced mTOR mRNA and protein expression. Inhibition of mTOR signalling with rapamycin reduced the expression of endogenous VIP and of VIP-induced S6 phosphorylation. Our findings support a role of VIP in the transport of glucose and neutral amino acids in cytotrophoblast cells through mTOR-regulated pathways and they are instrumental for understanding the physiological regulation of nutrient sensing by endogenous VIP at the maternal-foetal interface.

From decidualization to pregnancy progression: An overview of immune and metabolic effects of VIP

“…VIP is expressed in the human trophoblast cell lines JEG-3, BeWo, HTR-8/SVNeo and Swan 71. 18,78,[89][90][91] VPAC1 and VPAC2 receptors are expressed in these cell lines. 17,89,92 Both receptors are involved in autocrine and paracrine regulation of cytotrophoblast cells HTR-8/SVNeo and Swan 71 function through activating protein kinase A-cAMP response element (PKA-CRE) pathways and crosstalk signals.…”

“…VIP is expressed in the human trophoblast cell lines JEG‐3, BeWo, HTR‐8/SVNeo and Swan 71 18,78,89–91 . VPAC1 and VPAC2 receptors are expressed in these cell lines 17,89,92 .…”

Fetomaternal Expression of Glucose Transporters (GLUTs)—Biochemical, Cellular and Clinical Aspects

“…Moreover, observed effects in response to glucose treatment could be associated with the increased ERK 1/2 phosphorylation in the analyzed cells after the resistin stimulation [ 106 ]. Further, the vasoactive intestinal peptide (VIP) has the capacity to promote the GLUT1 expression and glucose transport in human cytotrophoblast cells through the mammalian target of the rapamycin (mTOR) signaling pathway [ 107 ]. Furthermore, the inhibition of mTOR signaling resulted in a significant reduction in GLUT3 mRNA and protein expression in the JEG-3 human choriocarcinoma cell line [ 108 ].…”

Decidual factors and vasoactive intestinal peptide guide monocytes to higher migration, efferocytosis and wound healing in term human pregnancy

“…9 VIP modulated trophoblast cell function exhibiting a promigratory and pro-invasive effect that depended on specific glucose uptake and mTOR activation in human cytotrophoblast cell lines in vitro. 10,11 Trophoblastic VIP enhanced apoptotic cell clearance by monocytes with increased production of IL-10. 5,7 Moreover VIP silencing in trophoblast cells prevented the conditioning of monocytes which showed reduced phagocytosis of apoptotic cells and IL-10 protein expression.…”

“…VIP has been assigned a regulatory role in early human pregnancy through targeting trophoblast, decidual cells and macrophages, 4,5 neutrophils 7,8 and Treg cells 9 . VIP modulated trophoblast cell function exhibiting a promigratory and pro‐invasive effect that depended on specific glucose uptake and mTOR activation in human cytotrophoblast cell lines in vitro 10,11 . Trophoblastic VIP enhanced apoptotic cell clearance by monocytes with increased production of IL‐10 5,7 .…”