Anandamide and cyclooxygenase-2 participate in vascular remodeling at the maternal-fetal interface

CAÑUMIL VA; SCOTTI L; FRANCHI A; MERESMAN G; PARBORELL MF; RIBEIRO ML

Simposio; International Symposium of Reproductive Health; 2021

Successful implantation and placentation requires vascular transformation of the uterus. A dynamic interaction between cells at the maternal-fetal interface is crucial for these processes. Anandamide (AEA) is an endocannabinoid that regulates embryo implantation and many of the placental functions. The uterine levels of AEA are primarily regulated by fatty acid amide hydrolase (FAAH), its degrading enzyme. Using in-vivo and in-vitro approaches we investigated the role of anandamide in the vascular remodeling of the uterus at early gestation. Also, ciclooxigenase- 2 (COX-2) participation was studied. First, Wistar rats received an intrauterine injection of URB-597 in day 5 of gestation (day of implantation). URB-597 is a highly selective inhibitor of FAAH. Control horns were injected with vehicle. Animals were euthanized in day 8. We observed that: (1) URB-597 increased fetal resorptions and induced aberrant embryo spacing and abortions, (2) URB-597 augmented the cross-sectional length of the uterine and arcuate arteries, and (3) Meloxicam (a highly selective COX-2 inhibitor) prevented URB-597 effects. Afterward, we studied the effect of AEA in the interaction between the endometrial stromal fibroblasts and the endothelial cells of the maternal vessels. Thus, human endometrial stromal cells (T-hESC) were incubated with AEA or AEA + meloxicam. AEA stimulated T-hESC migration in a concentration-dependent manner and COX-2 mediated this effect. To test endometrial fibroblasts-endothelial crosstalk, the endothelial cell line EA.hy926 was incubated with T-hESC conditioned medium. The conditioned media from AEA-induced T-hESC migration stimulated endothelial cells migration. Soluble factors derived from COX-2 pathway were involved in T-hESC and EA.hy926 interaction. Collectively, our results show the participation of AEA in the vascular remodeling that takes place in the uterus during early gestation by a mechanism that involves the COX-2 isoform.