Inhibition of fatty acid amide hydrolase leads to uterine vascular defects and decreased fertility in pregnant rats

Abstract

In brief: Dysregulation in anandamide homeostasis induces defects in the vascular adaptations of the uterus that threaten the continuity of pregnancy. We provide new evidence about the role of anandamide as a mediator in a critical event for early pregnancy, which is the vascular adaptation of the uterus.

Abstract: Successful pregnancy requires the vascular transformation of the uterus. Anandamide (AEA) regulates early gestation, but its role in uterine vascular adaptations is not fully elucidated. Besides, cyclooxygenase-2 (COX-2)-derived prostaglandins regulate angiogenesis at the implantation site. We investigated the relevance of AEA in the vascular transformations of the uterus in early gestation. In addition, we studied the participation of COX-2 in this process. Uterine AEA tone is controlled by its degrading enzyme, fatty acid amide hydrolase (FAAH). Thus, FAAH inhibition was used as a pharmacological tool to investigate the role of AEA in vivo. Wistar rats received an intrauterine injection of URB-597 (a highly selective FAAH inhibitor) on day 5 of gestation and were euthanized on day 8 of pregnancy. For in vitro studies, day 5 uterus was incubated with AEA. Meloxicam (a highly selective COX-2 inhibitor) was used to test the role of COX-2 in vivo and in vitro. URB-597 treatment augmented uterine and arcuate arteries' width and myometrium thickness. In addition, it increased the number of decidual microvessels and decreased their wall:lumen ratio. Thus, FAAH inhibition altered uterine macrovascular and microvascular adaptations. These alterations were associated with reduced fertility parameters. Meloxicam administration prevented URB-597 effects. In vitro, AEA augmented the production of prostaglandin F2alpha and E2 in a concentration-dependent manner. The pre-incubation with meloxicam blocked AEA stimulation. Our results highlight the importance of AEA tone for proper vascular adaptations of the uterus during early gestation and the relevance of COX-2 in this action.

Keywords: anandamide; cyclooxygenase-2; fatty acid amide hydrolase; fertility; uterine vascular adaptations.