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Endothelial deletion of ADAM10, a key regulator of Notch signaling, causes impaired decidualization and reduced fertility in female mice

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Abstract

During the initiation of pregnancy, the vasculature of the implantation site expands rapidly, yet little is known about this process or its role in fertility. Here, we report that endothelial-specific deletion of a disintegrin and metalloprotease 10 (ADAM10), an essential regulator of Notch signaling, results in severe subfertility in mice. We found that implantation sites develop until 5.5 days post conception (dpc) but are resorbed by 6.5 dpc in A10ΔEC mice. Analysis of the mutant implantation sites showed impaired decidualization and abnormal vascular patterning compared to controls. Moreover, RNA-seq analysis revealed changes in endothelial cell marker expression consistent with defective ADAM10/Notch signaling in samples from A10ΔEC mice, suggesting that this signaling pathways is essential for the physiological function of endometrial endothelial cells during early pregnancy. Our findings raise the possibility that impaired endothelial cell function could be a cause for repeated pregnancy loss (RPL) and infertility in humans.

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Acknowledgements

We thank Dr. Laurie Lacko, Orla O’Shea, Dr. Tania Panellini, Dr. Kat Hadjantonakis, Dr. Gisela Weskamp and Dr. Dragos Dasoveanu for help, advice and insightful suggestions during the course of this project. The Weill Cornell Genomics core performed the RNA-seq analysis presented here. This study was funded in part by NIH R01 GM64750 and NIH R35 GM134907 to C. Blobel and by NIH R01 HL082098 and the March of Dimes Research Foundation (Research Grant #6-FY14-411) to H. Stuhlmann. G. Farber was funded by American Heart Association Predoctoral Fellowship (#17PRE33380001). The measurements of serum hormone levels were performed by The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core which is supported by the Eunice Kennedy Shriver NICHD/NIH (NCTRI) Grant P50-HD28934.

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Authors and Affiliations

  1. Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA

    Nicole Lustgarten Guahmich, Gregory Farber, Dylan McNally & Carl P. Blobel

  2. Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY, USA

    Nicole Lustgarten Guahmich, David Redmond, Eleni Kallinos & Daylon James

  3. Research Institute of the McGill University Health Centre, Montréal, QC, Canada

    Shiva Shafiei & Daniel Dufort

  4. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA

    Heidi Stuhlmann

  5. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY, USA

    Carl P. Blobel

  6. Hospital for Special Surgery at Weill Cornell Medicine, 535 East 70th, New York, NY, 10021, USA

    Carl P. Blobel

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Contributions

NLG, GF and CB designed the experiments and prepared the manuscript. NLG harvested all tissues, maintained the mouse colony, performed immunofluorescence experiments and histopathology analysis. EK assisted with the histopathology. NLG and DJ prepared the samples for RNA sequencing and DR and DM helped with the analysis of the RNA-seq data. DD and SS performed the artificial decidualization assays and provided valuable advice and input. HS provided guidance and intellectual input throughout the project. All authors contributed to the editing of the manuscript.

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Correspondence to Carl P. Blobel.

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Lustgarten Guahmich, N., Farber, G., Shafiei, S. et al. Endothelial deletion of ADAM10, a key regulator of Notch signaling, causes impaired decidualization and reduced fertility in female mice. Angiogenesis 23, 443–458 (2020). https://doi.org/10.1007/s10456-020-09723-z

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