Vasoactive intestinal peptide induces metabolic rewiring of human-derived cytotrophoblast cells to promote cell migration

MERECH, FÁTIMA; LARA, BRENDA; RIOS, DAIANA; PAPARINI, DANIEL; RAMHORST, ROSANNA; HAUK, VANESA; PÉREZ LEIRÓS, CLAUDIA; VOTA, DAIANA

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

ELSEVIER SCIENCE BV

Año: 2025 vol. 1872

0167-4889

The placenta has an extraordinary metabolic rate with high oxygen consumption. Extravillous cytotrophoblastcells (EVT) metabolism and function are critical to sustain their invasive phenotype supporting fetal development. Deficient EVT function underlies pregnancy complications as preeclampsia (PE) and fetal growth restriction (FGR). The vasoactive intestinal peptide (VIP) promotes human cytotrophoblast cell migration andinvasion through mTOR signaling pathways suggesting its crucial role during placentation. Here we exploredfatty acid uptake as well as lipid and glucose metabolism in human-derived cytotrophoblast cell function uponVIP stimulation. We found that VIP induced long chain fatty acid (LCFAs) uptake along with the expression ofFATP2 transporter, CPT1 fatty acid oxidation (FAO)-rate limiting step importer, and lipid droplet accumulation.VIP induced the expression of glucose 6-P-dehydrogenase, a rate-limiting enzyme of the pentose phosphatepathway (PPP) and pyruvate dehydrogenase complex enzyme DLAT E2, without altering lactate secretion. Thismetabolic rewiring of trophoblast cells induced by VIP takes place without compromising mitochondrial functionor reactive oxygen species (ROS) production. Moreover, cytotrophoblast cell migration induced by VIP requiredthe three glycolysis, oxidative phosphorylation (OXPHOS) and FAO pathways. Our results provide evidencesupporting