HYPEROSMOLARITY INDUCES CAVEOLAE DISRUPTION AND INTERNALIZATION IMPAIRING HUMAN EXTRAVILLOUS TROPHOBLAST DIFFERENTIATION

MARTÍNEZ, NORA ALICIA

Congreso; Reunion Anual de Sociedades de Biociencias; 2022

The success of pregnancy depends on the normal placental development that involves the differentiation of the trophoblasts cells in the different linages. A group of trophoblast cells acquire an invasive phenotype (extravillous trophoblast-EVT) which can migrate and invade the decidua and myometrium. The EVTs remodel the spiral uterine arteries replacing the endothelial cells and acquiring an “endothelial-like phenotype”.Although these events are not entirely clear, it is known that they are tightly regulated in a spatiotemporal manner. Consequently, defects in these highly-coordinated processes in the early first trimester of gestation can lead to pathologies associated with placental insufficiency as fetal death, fetal growth restriction (FGR), and preeclampsia (PE).Many of the signaling pathways involved in trophoblast differentiation have receptors located in caveolae. These structures are small-specialized plasma membrane microdomains witch Caveolin-1 (Cav-1) is the major integral membrane protein required for its formation. We recently reported that an intact caveolar structure is necessary for adequate cell migration and tubulogenesis of the human extravillous trophoblast (EVT) cells.Emerging evidence supports, that hyperosmolarity induces the internalization of caveolae into the cytoplasm and accelerates their turnover. Therefore, the aim of this study was to evaluate the effect of hyperosmolarity on EVT differentiation and caveolae structure. EVT cells line (Swan 71) were cultured in complete Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12 and exposed to hyperosmolar condition (generated by the addition of 100 mM sucrose).Hyperosmolarity altered the EVT cell migration and the formation of tube-like structures.In addition, cell invasion was decreased along with a reduction in the latent and activeforms of matrix metalloproteinase-2 (MMP-2) secreted by these cells. With respect toCav-1 protein abundance, we found that hyperosmolarity enhanced its degradation bythe lysosomal pathway. Accordingly, in the hyperosmolar condition, we also observed asignificant increase in the number of vacuoles and the internalization of the caveolaeinto the cytoplasm. Taken together, our findings suggest that hyperosmolarity mayinduce caveolae internalization and increase their turnover, compromising the normaldifferentiation of EVT cells