Placental TRPV2 is indispensable for normal fetal development.

TRPV2 is a calcium-permeable ion channel with a broad expression pattern that contributes to neuronal outgrowth, immune response, and cardiac function. Mice lacking Trpv2 are more susceptible to perinatal lethality, a phenotype that cannot be explained by its previously allocated functions. We recently reported functional TRPV2 expression in mouse trophoblast cells and described temporal expression changes during placental development in mice. Here, we provide compelling evidence that TRPV2 plays a vital role in normal placental development, determining fetal size and survival. Specifically, Trpv2 is abundantly present in a subset of murine placental syncytiotrophoblast cells II (SynTII) during early development. Its absence results in region-specific loss of SynTII cells and fetal vascular invasion, severely affecting placental morphology. Consequently, global Trpv2 knockout mice suffer from fetal growth restriction and embryonic lethality, a phenotype found to be allocated to a non-redundant role in the trophoblast, but not in the embryo. CRISPR/Cas9-mediated Trpv2 deletion in mouse trophoblast stem cells identified a critical role of Trpv2 in the differentiation process towards SynTII cells, which was confirmed by the growth restriction phenotype in SynTII-specific Trpv2 knockout animals. TRPV2 expression was abundantly detected in human syncytiotrophoblast cells differentiated from trophoblast stem cells, suggesting a conserved role for TRPV2 in human trophoblast differentiation. Finally in the human placenta, TRPV2 expression was lower in early-onset fetal growth restriction compared to appropriately grown pregnancies. Taken together, our findings identify for the first time the indispensable role of TRPV2 during placental development, arbitrating fetal outcomes.