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 2

Increased trophoblast giant cells, regressed formation of ectoplacental cone, and failure of fetal blood vessel formation in implantation sites of Bmpr2 cKO female mice.

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Increased trophoblast giant cells, regressed formation of ectoplacental ...
(A) Deletion of uterine Bmpr2 induces an increase of PRL3D1-positive trophoblast giant cells and disruption of the normal structure of the layers. CP, chorionic plate; EPC, ectoplacental cone; GC, trophoblast giant cells; DEC, decidua. Scale bar: 500 #x003bc;m (left); 200 #x003bc;m (right). (B) Deletion of uterine Bmpr2 increases Prl3d1 and Mmp9 mRNA levels in E9 trophoblast cells (**P lt; 0.01). Data are mean #x000b1; SEM. (C and D) Regression of the ectoplacental cone and failure to compress the uterine lumen (LUM) in E9 implantation sites of Bmpr2 cKO uteri. KRT8, cytokeratin 8. Scale bar: 500 #x003bc;m (C); 200 #x003bc;m (D). (E) Deletion of uterine Bmpr2 decreases Cnr1 and Faah mRNA levels in E9 trophoblast cells (*P lt; 0.05; **P lt; 0.01). Data are mean #x000b1; SEM. (F) Increased apoptosis was detected in E9 invasive trophoblast cells from Bmpr2 cKO uteri by TUNEL assay. Scale bar: 500 #x003bc;m. (G) Impaired trophoblast invasion was detected in E9 implantation sites of Bmpr2 cKO uteri by immunostaining for PTGS2 and real-time quantitative PCR for Ptgs2 mRNA (**P lt; 0.01). Scale bar: 500 #x003bc;m. Data are mean #x000b1; SEM. (H) Impaired formation of fetal blood vessels was detected in E10 implantation sites of Bmpr2 cKO uteri. Arrowheads indicate fetal blood vessels. AL, allantois; SP, spongiotrophoblast cells; FV, fetal blood vessel; MV, maternal blood vessel. Scale bar: 500 #x003bc;m (left and middle); 200 #x003bc;m (right). (A and H) Higher-magnification images of the boxed regions are shown at right.