Overexpression of miR-210-3p Impairs Extravillous Trophoblast Functions Associated with Uterine Spiral Artery Remodeling.

Hsa-miR-210-3p has been reported to be upregulated in preeclampsia (PE); however, the functions of miR-210-3p in placental development are not fully understood, and, consequently, miR-210-3p's role in the pathogenesis of PE is still under investigation. In this study, we found that overexpression of miR-210-3p reduced trophoblast migration and invasion, extravillous trophoblast (EVT) outgrowth in first trimester explants, expression of endovascular trophoblast (enEVT) markers and the ability of trophoblast to form endothelial-like networks. In addition, miR-210-3p overexpression significantly downregulated the mRNA levels of interleukin-1B and -8, as well as CXC motif ligand 1. These cytokines have been suggested to play a role in EVT invasion and the recruitment of immune cells to the spiral artery remodeling sites. We also showed that caudal-related homeobox transcription factor 2 (CDX2) is targeted by miR-210-3p and that CDX2 downregulation mimicked the observed effects of miR-210-3p upregulation in trophoblasts. These findings suggest that miR-210-3p may play a role in regulating events associated with enEVT functions and its overexpression could impair spiral artery remodeling, thereby contributing to PE.

Role of EFNB2/EPHB4 signaling in spiral artery development during pregnancy: An appraisal.

EFNB2 and EPHB4, which belong to a large tyrosine kinase receptor superfamily, are molecular markers of arterial and venous blood vessels, respectively. EFNB2/EPHB4 signaling plays an important role in physiological and pathological angiogenesis, and its role in tumor vessel development has been extensively studied. Pregnancy and tumors share similar features, including continuous cell proliferation and increased demand for a blood supply. Our previous studies showed that Efnb2 and Ephb4 were expressed dynamically in the spiral arteries, uterine natural killer cells, and trophoblasts during mouse gestation Days 6.5-12.5. Moreover, uterine natural killer cells and trophoblasts are required for the modification of spiral arteries. Oxygen tension within the pregnant uterus, which contributes to the vascular development, also affects EFNB2 and EPHB4 expression. Considering the role of EFNB2/EPHB4 signaling in embryonic and tumor vascular development, and its dynamic expression in the decidua and placenta, we hypothesize that EFNB2 and EPHB4 are involved in the regulation of spiral artery remodeling. Investigating this hypothesis will help clarify the mechanisms of pathological pregnancy that may underlie abnormal spiral artery development.

Correlación de las curvas Doppler de arterias uterinas con el desarrollo puberal de los genitales internos de niñas y adolescentes: experiencia en un servicio de imagenología pediátrico / Correlation of uterine artery Doppler patterns and the development of the internal genitalia of girls and adolescents: experience in a pediatric imaging department

Ultrasound allows evaluate in girls, the internal genitals development and their follow up during puberty. Doppler of the uterine arteries (UA) has demonstrated be a complementary parameter to detect the onset of puberty. Objective: To show through our experience, the correlation between the internal genital development and the Doppler of UA morphology in girls and adolescents. We analyzed in 84 ultrasounds (US); uterine morphology and the relation body/cervix, endometrial thickness, ovarian volume and the pattern of Doppler UA. We obtained a relationship between the anatomic changes usually studied and the patterns of the Doppler UA, since childhood to puberty. Conclusion: The diastolic flow changes in the UA can be complementary for the diagnosis of the degree of puberty.

El ultrasonido permite la evaluación del desarrollo de los genitales internos en las niñas y seguimiento a través de la pubertad. La curva del Doppler de arterias uterinas (AU) ha demostrado ser un parámetro complementario en la detección del inicio de la pubertad.Objetivo: mostrar la correlación del desarrollo de los genitales internos, con la morfología de las curvas Doppler de AU en niñas y adolescentes a través de nuestra experiencia. Analizamos en 85 ultrasonidos (US); morfología uterina, relación cuerpo/cervix, grosor endometrial, volumen ovárico y morfología de la curva del Doppler de AU. Constatamos una asociaciónentre los cambios morfológico estudiados habitualmente con los distintos patrones de las curvas del Doppler desde la niñez a la pubertad. Conclusión: Los cambios en el flujodiastólico de las arterias uterinas permiten complementar el diagnóstico del grado de progreso de la pubertad.

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy.

In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.