BMPR2 is required for postimplantation uterine function and pregnancy maintenance
Takashi Nagashima, … , Francesco J. DeMayo, Martin M. Matzuk
Takashi Nagashima, … , Francesco J. DeMayo, Martin M. Matzuk
Published May 8, 2013
Citation Information: J Clin Invest. 2013;123(6):2539-2550. https://doi.org/10.1172/JCI65710.
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Research Article Reproductive biology

BMPR2 is required for postimplantation uterine function and pregnancy maintenance

Abstract

Abnormalities in cell-cell communication and growth factor signaling pathways can lead to defects in maternal-fetal interactions during pregnancy, including immunologic rejection of the fetal/placental unit. In this study, we discovered that bone morphogenetic protein receptor type 2 (BMPR2) is essential for postimplantation physiology and fertility. Despite normal implantation and early placental/fetal development, deletion of Bmpr2 in the uterine deciduae of mice triggered midgestation abnormalities in decidualization that resulted in abnormal vascular development, trophoblast defects, and a deficiency of uterine natural killer cells. Absence of BMPR2 signaling in the uterine decidua consequently suppressed IL-15, VEGF, angiopoietin, and corin signaling. Disruption of these pathways collectively lead to placental abruption, fetal demise, and female sterility, thereby placing BMPR2 at a central point in the regulation of several physiologic signaling pathways and events at the maternal-fetal interface. Since trophoblast invasion and uterine vascular modification are implicated in normal placentation and fetal growth in humans, our findings suggest that abnormalities in uterine BMPR2-mediated signaling pathways can have catastrophic consequences in women for the maintenance of pregnancy.

Authors

Takashi Nagashima, Qinglei Li, Caterina Clementi, John P. Lydon, Francesco J. DeMayo, Martin M. Matzuk

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Figure 4

Decidual cell proliferation defects in uteri of pregnant Bmpr2 cKO mice.

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Decidual cell proliferation defects in uteri of pregnant ...
(A) Deletion of uterine Bmpr2 decreases Prl3c1 and Prl8a2 mRNA levels in E9 decidual cells (*P lt; 0.05). Data are mean #x000b1; SEM. (B and C) Restricted decidual cell proliferation was detected in both MD and AMD compartments within E9 implantation sites of Bmpr2 cKO uteri by counting MKI67-positive cells without counterstaining (***P lt; 0.001). Scale bar: 1 mm (left); 300 #x003bc;m (middle and right); 100 #x003bc;m (insets). Data are mean #x000b1; SEM. (D) Representative histograms of flow cytometric analyses and calculated populations of S/G2 phase cells in isolated decidual cells from E9 implantation sites. Increased G1 phase and decreased S/G2 phase population in E9 implantation sites of Bmpr2 cKO uteri (**P lt; 0.01). Data are mean #x000b1; SEM. (E) Deletion of uterine Bmpr2 decreases Ccnd3 mRNA levels in E9 trophoblast cells (**P lt; 0.01). Data are mean #x000b1; SEM. (F) Reduced CCND3-positive cells were detected in E9 implantation sites of Bmpr2 cKO uteri without counterstaining. Scale bar: 500 #x003bc;m (left); 300 #x003bc;m (right); 100 #x003bc;m (inset). (G) Western blot analysis of isolated E9 decidual cells from Bmpr2 cKO uteri shows decreased expression of CCND3 but not pAKT and tAKT. ACTB expression was used as an internal control. (B and F) Higher-magnification images of the boxed regions are shown at right, and within these images, higher-magnification images of the boxed regions are shown as insets.