Anandamide targets aromatase: A breakthrough on human decidualization |
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| Institution: | 1. UCIBIO, REQUIMTE, Laboratório de Bioquímica, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal;2. UCIBIO, REQUIMTE, Laboratório de Bioquímica Computacional, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Portugal;1. Department of Biomedicine, Unit of Anatomy, Faculty of Medicine, University of Porto, Portugal;2. CINTESIS, Center for Health Technology and Services Research, Faculty of Medicine, University of Porto, Porto, Portugal;3. UCIBIO, REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia, University of Porto, Porto, Portugal;4. IUCS/CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Portugal;1. UCIBIO, REQUIMTE, Laboratory of Biochemistry, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Portugal;2. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy |
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| Abstract: | In each menstrual cycle endometrial stromal cells (hESC) proliferate and differentiate into specialized decidual cells, a process termed decidualization, which regulates endometrial receptivity. Decidualization is mainly controlled by sex ovarian hormones, estradiol (E2) and progesterone. E2 plays an important role in the expression of the progesterone receptor and promotes the endometrial stromal cells differentiation. Our group previously reported that anandamide (AEA) impairs decidualization through cannabinoid receptor 1 (CB1). In this study, we hypothesized whether AEA inhibitory effect on cell decidualization could be mediated through interaction with aromatase and consequent interference in estradiol production/signaling. We used an immortalized human endometrial stromal cell line (St-T1b) and human decidual fibroblasts (HdF) derived from human term placenta. In cells exposed to a differentiation stimulus, AEA-treatment prevents the increase of the expression of CYP19A1 gene encoding aromatase, E2 levels and of estradiol receptor expression, that are observed in differentiating cells. Regarding CYP19A1 mRNA levels, the effect was partially reverted by a CB1 receptor antagonist and by a COX2 inhibitor. In addition, we report that AEA presents anti-aromatase activity in placental microsomes, the nature of the inhibition being the uncommon mixed type as revealed by the kinetic studies. Structural analysis of the AEA-Aromatase complexes determined that AEA may bind to the active site pocket of the enzyme. In overall we report that AEA inhibits aromatase activity and may affect E2 signaling crucial for the decidualization process, indicating that a deregulation of the endocannabinoid system may be implicated in endometrial dysfunction and in fertility/infertility disorders. |
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