RESUMO
In female mammals, granulosa cells of the ovarian follicle differentiate into the corpus luteum after ovulation of the pregnable oocyte into the fallopian tube. During these differentiation processes several morphological alterations have to occur and the molecular basis is not fully understood. As an endpoint estradiol production from granulosa cells has to switch off in favor for progesterone production from the proceeding corpus luteum to sustain the developing embryo. Previously, we demonstrated that the multiligand receptor LOX-1 plays a critical role in steroid hormone synthesis of granulosa cells via intracellular calcium release from endoplasmic (ER)-dependent and ER-independent calcium pools. In the present study, we show that inhibition of LOX-1 leads to a rearrangement of ceramide from the basal membrane toward the Golgi apparatus. This activity is accomplished by a calcium-dependent phosphorylation of aromatase, the key step in estradiol production. Phosphorylated aromatase increased estradiol production in a dose-dependent manner. Our data indicate that the ceramide cascade is essential for proper granulosa cell function and ceramide redistribution serves as a first step in order to proceed with the prosperous differentiation into a corpus luteum.
Assuntos
Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Oócitos/citologia , Receptores Depuradores Classe E/genética , Animais , Bovinos , Ceramidas/metabolismo , Corpo Lúteo/citologia , Corpo Lúteo/metabolismo , Feminino , Hormônio Foliculoestimulante/metabolismo , Complexo de Golgi/genética , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Humanos , Oócitos/crescimento & desenvolvimento , Folículo Ovariano/citologia , Folículo Ovariano/metabolismo , Receptores Depuradores Classe E/antagonistas & inibidores , Transdução de SinaisRESUMO
Estradiol produced by ovarian granulosa cells triggers the luteinizing hormone surge which in turn initiates ovulation in female mammals. Disturbances in estradiol production from granulosa cells are a major reason for reproductive dysfunctions in dairy cows. Endogenous estradiol production might be altered by reactive oxygen species (ROS) such as oxidized low-density lipoprotein (ox-LDL). Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor of ox-LDL, leads to increased estrogenesis in granulosa cells. This activity is mediated by calcium release from endoplasmic reticulum (ER)-dependent and ER-independent calcium pools. Inhibition of the LOX-1 signal transduction pathway is followed by mitochondrial alterations. The membrane potential ΔΨ increases and the ROS production decreases in mitochondria after blocking LOX-1. Our data indicate that blocking the LOX-1 receptor signal pathway might be a promising way to improve steroid hormone concentrations in metabolically highly active female mammals and, therefore, to defend against reproductive dysfunctions in humans and animals.
Assuntos
Cálcio/metabolismo , Estradiol/biossíntese , Ovulação/metabolismo , Receptores Depuradores Classe E/genética , Animais , Bovinos , Feminino , Células da Granulosa/metabolismo , Humanos , Lipoproteínas LDL/metabolismo , Hormônio Luteinizante/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Depuradores Classe E/antagonistas & inibidores , Receptores Depuradores Classe E/metabolismo , Transdução de Sinais/genéticaRESUMO
F2-isoprostanes such as 8-iso-prostaglandin F2