Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta
Open accessAbstract
The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Endothelial cell dysfunction has been associated with placental pathology and disease states.
“Since endothelial cell dysfunction has been associated with placental pathology and disease states29–32,”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [29]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Steegers, E. A., von Dadelszen, P., Duvekot, J. J., & Pijnenborg, R. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60279-6 · Cited by 2,850 · see citing works
Latest Advances in Understanding Preeclampsia
Redman, C. W., & Sargent, I. L. (2005) · Science · doi:10.1126/science.1111726 · Cited by 2,607 · see citing works
Decidual NK cells regulate key developmental processes at the human fetal-maternal interface
Hanna, J. H., Goldman‐Wohl, D., Hamani, Y., Avraham, I., Greenfield, C., Natanson‐Yaron, S., Prus, D., Cohen‐Daniel, L., Arnon, T. I., Manaster, I., et al. (2006) · Nature Medicine · doi:10.1038/nm1452 · Cited by 1,690 · see citing works
The Uterine Spiral Arteries In Human Pregnancy: Facts and Controversies
Pijnenborg, R., Vercruysse, L., & HANSSENS, M. C. A. J. A. (2006) · Placenta · doi:10.1016/j.placenta.2005.12.006 · Cited by 1,201 · see citing works
Immunology of placentation in eutherian mammals
Moffett, A., & Loke, C. (2006) · Nature reviews. Immunology · doi:10.1038/nri1897 · Cited by 843 · see citing works
Interactions between Trophoblast Cells and the Maternal and Fetal Circulation in the Mouse Placenta
Adamson, S. L., Lu, Y., Whiteley, K. J., Holmyard, D., Hemberger, M., Pfarrer, C., & Cross, J. C. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0773 · Cited by 617 · see citing works
Development of Structures and Transport Functions in the Mouse Placenta
Watson, E. D., & Cross, J. C. (2005) · Physiology · doi:10.1152/physiol.00001.2005 · Cited by 583 · see citing works
Novel and Conventional Biomarkers for Prediction of Incident Cardiovascular Events in the Community
Melander, O. (2009) · JAMA · doi:10.1001/jama.2009.943 · Cited by 552 · see citing works
Smith, S. D., Dunk, C., Aplin, J., Harris, L. K., & Jones, R. L. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080995 · Cited by 466 · see citing works
Pijnenborg, R., Robertson, W. B., Brosens, I. A., & Dixon, G. (1981) · Placenta · doi:10.1016/s0143-4004(81)80042-2 · Cited by 435 · see citing works
Diverse subtypes and developmental origins of trophoblast giant cells in the mouse placenta
Simmons, D. G., Fortier, A., & Cross, J. C. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.01.009 · Cited by 399 · see citing works
Immune cells in the placental bed
Bulmer, J. N., Williams, P. J., & Lash, G. E. (2009) · The International Journal of Developmental Biology · doi:10.1387/ijdb.082763jb · Cited by 365 · see citing works
Determinants of trophoblast lineage and cell subtype specification in the mouse placenta
Simmons, D. G., & Cross, J. C. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.05.010 · Cited by 357 · see citing works
Caron, K. M., & Smithies, O. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.615 · Cited by 346 · see citing works
Self-citationCigarette smoking during pregnancy and risk of preeclampsia: A systematic review
Conde‐Agudelo, A., Althabe, F., Belizán, J. M., & Kafury-Goeta, A. C. (1999) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(99)70341-8 · Cited by 335 · see citing works
Development and function of trophoblast giant cells in the rodent placenta
Hu, D., & Cross, J. C. (2009) · The International Journal of Developmental Biology · doi:10.1387/ijdb.082768dh · Cited by 307 · see citing works
The placenta: transcriptional, epigenetic, and physiological integration during development
Maltepe, E., Bakardjiev, A. I., & Fisher, S. J. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41211 · Cited by 298 · see citing works
Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene
Shindo, T., Kurihara, Y., Nishimatsu, H., Moriyama, N., Kakoki, M., Wang, Y.-H., Imai, Y., Ebihara, A., Kuwaki, T., Ju, K., et al. (2001) · Circulation · doi:10.1161/hc4101.097111 · Cited by 273 · see citing works
Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones
Croy, B. A., Heuvel, M. J. V. D., Borzychowski, A. M., & Tayade, C. (2006) · Immunological Reviews · doi:10.1111/j.1600-065x.2006.00447.x · Cited by 273 · see citing works
Adrenomedullin signaling is necessary for murine lymphatic vascular development
Fritz-Six, K. L., Dunworth, W. P., Li, M., & Caron, K. M. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33302 · Cited by 261 · see citing works
Self-citationNatural killer cell-triggered vascular transformation: maternal care before birth?
Zhang, J., Chen, Z., Smith, G. N., & Croy, B. A. (2010) · Cellular and Molecular Immunology · doi:10.1038/cmi.2010.38 · Cited by 238 · see citing works
Croy, B. A., He, H., Esadeg, S., Wei, Q., McCartney, D. J., Zhang, J., Borzychowski, A. M., Ashkar, A. A., Black, G. P., Evans, S., et al. (2003) · Reproduction · doi:10.1530/rep.0.1260149 · Cited by 234 · see citing works
REVIEW ARTICLE: The Unique Properties of Uterine NK Cells
Manaster, I., & Mandelboim, O. (2010) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.2009.00794.x · Cited by 215 · see citing works
Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua
Lash, G. E., Robson, S. C., & Bulmer, J. N. (2010) · Placenta · doi:10.1016/j.placenta.2009.12.022 · Cited by 214 · see citing works
Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth
Madeja, Z. E., Yadi, H., Apps, R., Boulenouar, S., Roper, S. J., Gardner, L., Moffett, A., Colucci, F., & Hemberger, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005342108 · Cited by 163 · see citing works
Fukui, A., Funamizu, A., Yokota, M., Yamada, K., Nakamua, R., Fukuhara, R., Kimura, H., & Mizunuma, H. (2011) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2011.04.006 · Cited by 159 · see citing works
Ultrastructural Studies of Implantation Sites from Mice Deficient in Uterine Natural Killer Cells
Greenwood, J. D., Minhas, K., Santo, J. P. D., MAKITA, M., Kiso, Y., & Croy, B. A. (2000) · Placenta · doi:10.1053/plac.2000.0556 · Cited by 155 · see citing works
Red‐Horse, K., Rivera, J., Schanz, A., Zhou, Y., Winn, V., Kapidzic, M., Maltepe, E., Okazaki, K., Kochman, R., Vo, K. C., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27306 · Cited by 155 · see citing works
Dackor, R. T., Fritz-Six, K. L., Dunworth, W. P., Gibbons, C. L., Smithies, O., & Caron, K. M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.7.2511-2518.2006 · Cited by 146 · see citing works
Self-citationSalvatore, C., Hershey, J. C., Corcoran, H. A., Fay, J. F., Johnston, V. K., Moore, E. L., Mosser, S. D., Burgey, C. S., Paone, D. V., Shaw, A. W., et al. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.130344 · Cited by 146 · see citing works
Trophoblast‐mediated spiral artery remodelling: a role for apoptosis
Whitley, G. S. J., & Cartwright, J. E. (2009) · Journal of Anatomy · doi:10.1111/j.1469-7580.2008.01039.x · Cited by 145 · see citing works
Naruse, K., Lash, G. E., Innes, B., et al. (2008) · Human Reproduction · doi:10.1093/humrep/den408 · Cited by 145 · see citing works
CGRP antagonists: unravelling the role of CGRP in migraine
Doods, H. N., Arndt, K., Rudolf, K. D., & Just, S. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.10.005 · Cited by 141 · see citing works
Unique Receptor Repertoire in Mouse Uterine NK cells
Yadi, H., Burke, S., Madeja, Z. E., Hemberger, M., Moffett, A., & Colucci, F. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.9.6140 · Cited by 140 · see citing works
Fraser, R., Whitley, G. S. J., Johnstone, A. P., Host, A. J., Sebire, N. J., Thilaganathan, B., & Cartwright, J. E. (2012) · The Journal of Pathology · doi:10.1002/path.4057 · Cited by 132 · see citing works
Croy, B. A., Chen, Z., Hofmann, A. P., Lord, E. M., Sedlacek, A. L., & Gerber, S. A. (2012) · Biology of Reproduction · doi:10.1095/biolreprod.112.102830 · Cited by 120 · see citing works
Li, M., Yee, D., Magnuson, T., Smithies, O., & Caron, K. M. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28462 · Cited by 106 · see citing works
Self-citationAtypical E2F Repressors and Activators Coordinate Placental Development
Ouseph, M. M., Li, J., Chen, H., Pécot, T., Wenzel, P. L., Thompson, J. C., Comstock, G., Chokshi, V., Byrne, M., Forde, B., et al. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.01.013 · Cited by 104 · see citing works
Hu, D., & Cross, J. C. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.07.036 · Cited by 93 · see citing works
Recent advances in understanding immunology of reproductive failure
Makrigiannakis, A., Petsas, G. K., Tóth, B., Relakis, K., & Jeschke, U. (2011) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2011.03.006 · Cited by 75 · see citing works
Analysis of Uterine Natural Killer Cells in Mice
Croy, B. A., Zhang, J., Tayade, C., et al. (2009) · Methods in molecular biology · doi:10.1007/978-1-60761-362-6_31 · Cited by 74 · see citing works
Angiogenic factors and preeclampsia
Steinberg, G., Khankin, E. V., & Karumanchi, S. A. (2009) · Thrombosis Research · doi:10.1016/s0049-3848(09)70020-9 · Cited by 72 · see citing works
Yotsumoto, S., Shimada, T., Cui, C., Nakashima, H., Fujiwara, H., & Ko, M. S. H. (1998) · Developmental Biology · doi:10.1006/dbio.1998.9073 · Cited by 71 · see citing works
Adrenomedullin stabilizes the lymphatic endothelial barrier in vitro and in vivo
Dunworth, W. P., Fritz-Six, K. L., & Caron, K. M. (2008) · Peptides · doi:10.1016/j.peptides.2008.09.009 · Cited by 70 · see citing works
Self-citationHewitt, S. C., Collins, J. B., Grissom, S. F., et al. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0142 · Cited by 70 · see citing works
Adrenomedullin induces lymphangiogenesis and ameliorates secondary lymphoedema
Jin, D., Harada, K., Ohnishi, S., Yamahara, K., Kangawa, K., & Nagaya, N. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn228 · Cited by 68 · see citing works
Placental and Fetal Growth and Development in Late Rat Gestation Is Dependent on Adrenomedullin1
Witlin, A. G., Li, Z.-Y., Wimalawansa, S. J., et al. (2002) · Biology of Reproduction · doi:10.1095/biolreprod.101.002196 · Cited by 63 · see citing works
Watanabe, H., Takahashi, E., Kobayashi, M., Goto, M., Krust, A., Chambon, P., & Iguchi, T. (2006) · Journal of Molecular Endocrinology · doi:10.1677/jme.1.01825 · Cited by 58 · see citing works
Burke, S. D., Barrette, V. F., Gravel, J., Carter, A. L. I., Hatta, K., Zhang, J., Chen, Z., Leno‐Durán, E., Bianco, J., Leonard, S., et al. (2010) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.2010.00818.x · Cited by 57 · see citing works
Moderate smoking during pregnancy is associated with a reduced risk of preeclampsia
Lindqvist, P. G., & Maršál, K. (1999) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1034/j.1600-0412.1999.780806.x · Cited by 51 · see citing works
Portal‐Núñez, S., Shankavaram, U. T., Rao, M., Datrice, N., Atay, S. M., Aparicio, M., Camphausen, K. A., Fernández‐Salguero, P. M., Chang, H., Lin, P., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0818 · Cited by 50 · see citing works
Hoopes, S. L., Willcockson, H. H., & Caron, K. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045261 · Cited by 49 · see citing works
Self-citationThota, C. (2003) · Biology of Reproduction · doi:10.1095/biolreprod.103.015628 · Cited by 48 · see citing works
Adrenomedullin and pregnancy: perspectives from animal models to humans
Lenhart, P., & Caron, K. M. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.02.007 · Cited by 45 · see citing works
Self-citationHaploinsufficiency for Adrenomedullin Reduces Pinopodes and Diminishes Uterine Receptivity in Mice1
Li, M., Wu, Y., & Caron, K. M. (2008) · Biology of Reproduction · doi:10.1095/biolreprod.108.069336 · Cited by 45 · see citing works
Self-citationCathepsin proteases have distinct roles in trophoblast function and vascular remodelling
Screen, M., Dean, W., Cross, J. C., & Hemberger, M. (2008) · Development · doi:10.1242/dev.025627 · Cited by 44 · see citing works
Emerging Functions of Placental Cathepsins
Mason, R. W. (2008) · Placenta · doi:10.1016/j.placenta.2008.02.006 · Cited by 39 · see citing works
Caron, K. M., Hagaman, J. R., Nishikimi, T., Kim, H., & Smithies, O. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611365104 · Cited by 34 · see citing works
Self-citationSayers, R. L., Sundberg-Smith, L. J., Rojas, M. M., et al. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.175455 · Cited by 34 · see citing works
Smoking during pregnancy influences the maternal immune response in mice and humans
Prins, J. R., Hylkema, M. N., Erwich, J. J., et al. (2012) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2012.04.017 · Cited by 33 · see citing works
Ishimitsu, T., Hosoya, K., Tsukada, K., Minami, J., Futoh, Y., Ono, H., Ohrui, M., Hino, J., Kangawa, K., & Matsuoka, H. (2001) · Hypertension · doi:10.1161/01.hyp.38.1.9 · Cited by 31 · see citing works
Kobayashi, Y., Nakayama, T., Naoyuki, S. A. T. O., Izumi, Y., Kokubun, S., & Soma, M. (2005) · Hypertension Research · doi:10.1291/hypres.28.229 · Cited by 27 · see citing works
Moderate smoking during pregnancy is associated with a reduced risk of preeclampsia
Lindqvist, P. G., & Maršál, K. (1999) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1080/j.1600-0412.1999.780806.x · Cited by 25 · see citing works
Pure Strain Mice Born to Hybrid Mothers Following Ovarian Transplantation
Russell, W. L., & Hurst, J. G. (1945) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.31.9.267 · Cited by 21 · see citing works
Bao, S. H., Shuai, W., Tong, J., Wang, L., Chen, P., & Sun, J. (2012) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2012.08.005 · Cited by 20 · see citing works
Ross, G. R., Chauhan, M., Gangula, P. R., Reed, L. C., Thota, C. S., & Yallampalli, C. (2005) · Endocrinology · doi:10.1210/en.2005-0664 · Cited by 20 · see citing works
Regulation by hypoxia of adrenomedullin output and expression in human trophoblast cells
Marinoni, E., Pacioni, K., Sambuchini, A., Moscarini, M., Letizia, C., & Iorio, R. D. (2010) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2010.10.013 · Cited by 19 · see citing works
Beiswenger, T. R., Feng, L., Brown, H. L., et al. (2012) · Reproductive Sciences · doi:10.1177/1933719111426600 · Cited by 17 · see citing works
Ross, G. R., & Yallampalli, C. (2006) · Biology of Reproduction · doi:10.1095/biolreprod.106.053777 · Cited by 15 · see citing works
Sundara, Y. T. (2011) · Molecular Medicine Reports · doi:10.3892/mmr.2011.633 · Cited by 9 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [54]Manaster I, Mandelboim O. The unique properties of uterine NK cells. Am J Reprod Immunol . 2010; 63(6):434-444.
Cited by
Sorted by citations
Brown, J. L., Sones, J. L., Angulo, C. N., Abbott, K., Miller, A. D., Boehm, U., & Roberson, M. S. (2019) · Scientific Reports · doi:10.1038/s41598-019-45997-0 · Cited by 13 · see citing works
- Authors
- Li, M., Schwerbrock, N. M. J., Lenhart, P. M., Fritz-Six, K. L., Kadmiel, M., Christine, K. S., Kraus, D. M., Espenschied, S. T., Willcockson, H. H., Mack, C. P., & Caron, K. M.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Duke University (US)
- Corresponding author
- Caron, Kathleen M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-05-01
- Volume
- 123
- Issue
- 6
- Pages
- 2408-2420
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3668816
- OpenAlex
- W2127222493
- Cited by
- 65
- References
- 70
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 2 · 2015: 5 · 2014: 13 · 2013: 2
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL070953, R01HL109607, R01HL091973)
- National Cancer Institute (P30CA016086)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD46970, HD-060860, R01HD046970, ARRA-HD060860-01S1, R01HD060860)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Keywords
- adrenomedullin, spiral artery remodeling, preeclampsia, uterine NK cells, trophoblast, placenta, maternal-fetal interface, innate immunity, vascular smooth muscle cell apoptosis, chemokines, matrix metalloproteinases, re-endothelialization, biomarkers
- MeSH terms
- Animals, Decidua, Female, Fetus, Humans, Immunity, Innate, Killer Cells, Natural, Male, Maternal-Fetal Exchange, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Phenotype, Placenta, Pre-Eclampsia, Pregnancy, Trophoblasts, Giant Cells, Apoptosis, Mice, Knockout, Chemokines, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Myocytes, Smooth Muscle, Mice, Adrenomedullin, Mice, 129 Strain, Receptors, Adrenomedullin, Calcitonin Receptor-Like Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
