Antagonisation of Prokineticin Receptor-2 Attenuates Preeclampsia Symptoms

Preeclampsia (PE) is the most threatening pathology of human pregnancy. Placenta from PE patients releases harmful factors that contribute to the exacerbation of the disease. Among these factors is the prokineticin1 (PROK1) and its receptor, PROKR2 that we identified as a mediators of PE. Here we tested the effects of PKRA, an antagonist of PROKR2, on the attenuation of PE symptoms. We used the genetic PE mouse model, STOX1 that overexpresses Stox1 gene in a heterozygosis manner in the placenta. This model allowed exploiting two genotypes of the offspring, those that overexpress the Stox1 gene, and the WT that grow in a PE environment (STE). We characterised the effect PKRA (1 mu M) on the attenuation of PE symptoms and compared its effects on STOX1 and STE placentas. We also used STOX1 overexpressing trophoblast cells to decipher the PROK1-underlying mechanism. We demonstrated that (i) antagonisation of PROKR2 attenuated PE-mediated hypertension and proteinuria, (ii) STE placentas and foetuses exhibited better outcomes in response to PKRA, (iii) the secretome of STOX1-trophoblasts impacted the integrity of the fetal vasculature that was attenuated by PKRA treatment. This study demonstrates the direct involvement of the PROK1 in PE and identifies PKRA as a promising therapy for PE.