Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy (original) (raw)

• Letter
• Published: 21 March 2012
• Wei Wang1 na1 nAff6,
• Ningzheng Dong2,3 na1,
• Jinglei Lou1 na1,
• Dinesh Kumar Srinivasan1 nAff6,
• Weiwei Cheng4,
• Xiaoyi Huang4,
• Meng Liu2,
• Chaodong Fang2,
• Jianhao Peng1,
• Shenghan Chen1,
• Shannon Wu1,
• Zhenzhen Liu2,
• Liang Dong2,
• Yiqing Zhou2 &
• …
• Qingyu Wu1,2

Nature volume 484, pages 246–250 (2012)Cite this article

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Abstract

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 unclear1,2. 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 pressure3. Unexpectedly, corin expression was detected in the pregnant uterus4. 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.

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Acknowledgements

We thank J. Robbins for the α-myosin heavy chain promoter construct and L. Zhang for help with statistical analysis. This work was partly supported by grants from the Ralph Wilson Medical Foundation, the Bakken Heart-Brain Institute and the National Institutes of Health (HL089298, HD064634), and by grants from the National Natural Science Foundation of China (31070716, 81170247 and 31161130356) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Author notes

1. Yujie Cui, Wei Wang & Dinesh Kumar Srinivasan
   Present address: Present address: School of Laboratory Science, Tianjin Medical University, Tianjin 300203, China (Y.C.); Department of Cardiology, Peking Union Medical College, Beijing 100730, China (W.W.); Lee Kong Chian School of Medicine, Singapore 637553 (D.K.S.).,
2. Yujie Cui, Wei Wang, Ningzheng Dong and Jinglei Lou: These authors contributed equally to this work.

Authors and Affiliations

1. Molecular Cardiology, Nephrology and Hypertension, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA,
   Yujie Cui, Wei Wang, Jinglei Lou, Dinesh Kumar Srinivasan, Jianhao Peng, Shenghan Chen, Shannon Wu & Qingyu Wu
2. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou 215123, China,
   Ningzheng Dong, Meng Liu, Chaodong Fang, Zhenzhen Liu, Liang Dong, Yiqing Zhou & Qingyu Wu
3. Key Lab of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, 188 Shi Zhi Street, Suzhou 215006, China,
   Ningzheng Dong
4. The International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China,
   Weiwei Cheng & Xiaoyi Huang

Authors

1. Yujie Cui
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2. Wei Wang
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3. Ningzheng Dong
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4. Jinglei Lou
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5. Dinesh Kumar Srinivasan
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6. Weiwei Cheng
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7. Xiaoyi Huang
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8. Meng Liu
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9. Chaodong Fang
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10. Jianhao Peng
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11. Shenghan Chen
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12. Shannon Wu
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13. Zhenzhen Liu
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14. Liang Dong
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15. Yiqing Zhou
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16. Qingyu Wu
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Contributions

Y.C., W.W., N.D., J.L., D.K.S., M.L., C.F., J.P., S.C., S.W., Z.L. and L.D. designed and performed experiments. N.D., W.C. and X.H. collected patient samples and analysed clinical data. Q.W. conceived the study and designed experiments. Y.Z. and Q.W. wrote the manuscript. All authors analysed and interpreted data, and critically read the manuscript.

Corresponding author

Correspondence toQingyu Wu.

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Cui, Y., Wang, W., Dong, N. et al. Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy.Nature 484, 246–250 (2012). https://doi.org/10.1038/nature10897

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• Received: 21 May 2010
• Accepted: 25 January 2012
• Published: 21 March 2012
• Issue Date: 12 April 2012
• DOI: https://doi.org/10.1038/nature10897

Editorial Summary

Role of corin in pre-eclampsia

Corin is a cardiac protease that activates the cardiac hormone atrial natriuretic peptide (ANP), which lowers blood pressure. Corin expression has also been detected in the uterus. Qingyu Wu and colleagues now find that corin and ANP are involved in trophoblast invasion and spiral artery remodelling during pregnancy, and that loss of corin from the uterus causes pre-eclampsia-like symptoms in mice. The authors further show that pregnant women with pre-eclampsia have lower uterine levels of corin expression than women with normal pregnancies. They identify two mutations that reduce corin activity in pre-eclamptic patients.