While placental functioning arbitrates fetal outcome, the molecular players that underpin normal placental development remain poorly understood. Here, we provide evidence that the Transient Receptor Potential Vanilloid 2 (TRPV2) channel plays an important role in normal placental development, determining fetal size and survival. Its absence severely affects placental morphology, causing fetal growth restriction and embryonic lethality, which was 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 demonstrated that Trpv2 contributes to the differentiation towards Syncytiotrophoblast layer II (SynTII) cells, which was confirmed by the growth restriction phenotype in SynTII-specific Trpv2 knockout animals. Finally, TRPV2 was functionally expressed in human trophoblast cells and enriched in trophoblast populations undergoing syncytial differentiation. Together, our findings identify an important role for TRPV2 during placental development and consequently fetal outcomes.

Endometriosis-associated pain has debilitating effects on the quality of life of patients. Despite its high prevalence in reproductive-aged women, the pathophysiology is still unknown, impeding the development of targeted treatment approaches. The prospective ExPAND study proposes the neurosteroids pregnenolone sulphate (PS) and dehydroepiandrosterone sulphate (DHEAS) as potential contributors to endometriosis-associated pain, due to their agonistic action at the pain-related ion channel TRPM3. To this end, endometrium, deep endometriosis lesions, and peritoneal fluid were prospectively collected in four demarcated patient groups, which were characterised based on their pain symptoms, as scored via the WERF-EPHect questionnaire, i.e., (1) control (n = 44), (2) endometriosis patients with no pain symptoms (n = 24), (3) with only severe dysmenorrhea (n = 54), or (4) with both severe dysmenorrhea and non-cyclic pelvic pain (n = 78). Tissue mRNA expression levels of steroidogenic enzymes were investigated and showed significantly increased levels of CYP17A1 in the endometrium of patients with severe pain symptoms compared to control tissue. In addition, liquid chromatography with tandem mass spectrometry (LC-MS/MS) was performed to investigate neurosteroid concentrations in the peritoneal fluid. Both neurosteroids PS and DHEAS were present in the peritoneal fluid at concentrations that are known to stimulate TRPM3 activity in vitro. Finally, using microfluorimetric Ca²⁺ imaging, we demonstrate that both DHEAS and PS stimulate human stem-cell-derived sensory neurons in a TRPM3-dependent manner. Taken together, these data indicate a potential contribution of steroidogenesis and TRPM3 in endometriosis-associated pain.