Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Hypertension, proteinuria and renal pathology in pregnant Corin knockout and knockout/transgenic mice.
Figure 2: Impaired trophoblast invasion and spiral artery remodelling in Corin knockout and knockout/transgenic mice.
Figure 3: Hypertension, proteinuria and uteroplacental pathology in pregnant ANP knockout mice.
Figure 4: ANP-stimulated human trophoblast invasion, and impaired uterine Corin expression and Corin mutations in pre-eclamptic patients.

References

  1. Pijnenborg, R., Vercruysse, L. & Hanssens, M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27, 939–958 (2006)

    Article  CAS  Google Scholar 

  2. Red-Horse, K. et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J. Clin. Invest. 114, 744–754 (2004)

    Article  CAS  Google Scholar 

  3. Wu, Q., Xu-Cai, Y. O., Chen, S. & Wang, W. Corin: new insights into the natriuretic peptide system. Kidney Int. 75, 142–146 (2009)

    Article  CAS  Google Scholar 

  4. Yan, W., Sheng, N., Seto, M., Morser, J. & Wu, Q. Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart. J. Biol. Chem. 274, 14926–14935 (1999)

    Article  CAS  Google Scholar 

  5. Lain, K. Y. & Roberts, J. M. Contemporary concepts of the pathogenesis and management of preeclampsia. J. Am. Med. Assoc. 287, 3183–3186 (2002)

    Article  Google Scholar 

  6. Sibai, B., Dekker, G. & Kupferminc, M. Pre-eclampsia. Lancet 365, 785–799 (2005)

    Article  Google Scholar 

  7. Brosens, I. A., Robertson, W. B. & Dixon, H. G. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet. Gynecol. Annu. 1, 177–191 (1972)

    CAS  PubMed  Google Scholar 

  8. Kaufmann, P., Black, S. & Huppertz, B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol. Reprod. 69, 1–7 (2003)

    Article  CAS  Google Scholar 

  9. Norwitz, E. R., Schust, D. J. & Fisher, S. J. Implantation and the survival of early pregnancy. N. Engl. J. Med. 345, 1400–1408 (2001)

    Article  CAS  Google Scholar 

  10. Kanasaki, K. et al. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature 453, 1117–1121 (2008)

    Article  ADS  CAS  Google Scholar 

  11. Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004)

    Article  CAS  Google Scholar 

  12. Redman, C. W. & Sargent, I. L. Latest advances in understanding preeclampsia. Science 308, 1592–1594 (2005)

    Article  ADS  CAS  Google Scholar 

  13. Venkatesha, S. et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nature Med. 12, 642–649 (2006)

    Article  CAS  Google Scholar 

  14. Zhou, C. C. et al. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nature Med. 14, 855–862 (2008)

    Article  CAS  Google Scholar 

  15. Yan, W., Wu, F., Morser, J. & Wu, Q. Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme. Proc. Natl Acad. Sci. USA 97, 8525–8529 (2000)

    Article  ADS  CAS  Google Scholar 

  16. Chan, J. C. et al. Hypertension in mice lacking the proatrial natriuretic peptide convertase corin. Proc. Natl Acad. Sci. USA 102, 785–790 (2005)

    Article  ADS  CAS  Google Scholar 

  17. Dries, D. L. et al. Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension. Circulation 112, 2403–2410 (2005)

    Article  CAS  Google Scholar 

  18. Davisson, R. L. et al. Discovery of a spontaneous genetic mouse model of preeclampsia. Hypertension 39, 337–342 (2002)

    Article  CAS  Google Scholar 

  19. John, S. W. et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267, 679–681 (1995)

    Article  ADS  CAS  Google Scholar 

  20. Kuhn, M. et al. The natriuretic peptide/guanylyl cyclase—a system functions as a stress-responsive regulator of angiogenesis in mice. J. Clin. Invest. 119, 2019–2030 (2009)

    Article  CAS  Google Scholar 

  21. Tokudome, T. et al. Impaired recovery of blood flow after hind-limb ischemia in mice lacking guanylyl cyclase-A, a receptor for atrial and brain natriuretic peptides. Arterioscler. Thromb. Vasc. Biol. 29, 1516–1521 (2009)

    Article  CAS  Google Scholar 

  22. Dong, N. et al. Plasma soluble corin in patients with heart failure. Circ. Heart Fail. 3, 207–211 (2010)

    Article  Google Scholar 

  23. Jiang, J. et al. Ectodomain shedding and autocleavage of the cardiac membrane protease corin. J. Biol. Chem. 286, 10066–10072 (2011)

    Article  CAS  Google Scholar 

  24. Pan, J. et al. Genomic structures of the human and murine corin genes and functional GATA elements in their promoters. J. Biol. Chem. 277, 38390–38398 (2002)

    Article  CAS  Google Scholar 

  25. Knappe, S., Wu, F., Madlansacay, M. R. & Wu, Q. Identification of domain structures in the propeptide of corin essential for the processing of proatrial natriuretic peptide. J. Biol. Chem. 279, 34464–34471 (2004)

    Article  CAS  Google Scholar 

  26. Wang, W. et al. Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity. Circ. Res. 103, 502–508 (2008)

    Article  CAS  Google Scholar 

  27. Irons, D. W., Baylis, P. H., Butler, T. J. & Davison, J. M. Atrial natriuretic peptide in preeclampsia: metabolic clearance, sodium excretion and renal hemodynamics. Am. J. Physiol. 273, F483–F487 (1997)

    CAS  PubMed  Google Scholar 

  28. Tihtonen, K. M., Koobi, T., Vuolteenaho, O., Huhtala, H. S. & Uotila, J. T. Natriuretic peptides and hemodynamics in preeclampsia. Am. J. Obstet. Gynecol. 196, 328.e1–328.e7 (2007)

    Article  Google Scholar 

  29. Chen, S. et al. Protease corin expression and activity in failing hearts. Am. J. Physiol. Heart Circ. Physiol. 299, H1687–H1692 (2010)

    Article  CAS  Google Scholar 

  30. Liao, X., Wang, W., Chen, S. & Wu, Q. Role of glycosylation in corin zymogen activation. J. Biol. Chem. 282, 27728–27735 (2007)

    Article  CAS  Google Scholar 

  31. Dong, N. et al. Effects of anticoagulants on human plasma soluble corin levels measured by ELISA. Clin. Chim. Acta 411, 1998–2003 (2010)

    Article  CAS  Google Scholar 

  32. Wu, F., Yan, W., Pan, J., Morser, J. & Wu, Q. Processing of pro-atrial natriuretic peptide by corin in cardiac myocytes. J. Biol. Chem. 277, 16900–16905 (2002)

    Article  CAS  Google Scholar 

  33. Qi, X., Jiang, J., Zhu, M. & Wu, Q. Human corin isoforms with different cytoplasmic tails that alter cell surface targeting. J. Biol. Chem. 286, 20963–20969 (2011)

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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 to Qingyu Wu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-8 and Supplementary Tables 1-2. (PDF 605 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10897

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing