Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Mar 21;484(7393):246-50.
doi: 10.1038/nature10897.

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

Affiliations

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

Yujie Cui et al. Nature. .

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 unclear. 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 pressure. Unexpectedly, corin expression was detected in the pregnant uterus. 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Hypertension, proteinuria and renal pathology in pregnant corin ko and ko/Tg mice
a, Corin mRNA expression in mouse uteruses. b, Corin Tg construct. pA: poly A. c, d, Western analysis of corin protein in wt, corin ko and ko/Tg mice. e, Blood pressure (BP) (mean ± s.d.) in np females. BP increased in corin ko (f) and ko/Tg (g) mice in pregnancy. Data represent mean ± s.d. *P<0.05 vs. wt of the same time point. †P<0.05 vs. np level of the same genotype. h, Similar BP changes in corin ko females mated with ko or wt males. i, Late gestational proteinuria in corin ko and ko/Tg mice. Data represent mean ± s.d. **P<0.01, n=7-8 per group. j, Renal ischemia in pregnant corin ko and ko/Tg mice, shown in H&E (i-iii), Masson trichrome (iv-vi) or PAS (vii-ix) stained E18.5 sections. bar: 20 μm. Red blood cells (yellow arrows) and open capillaries (red arrows) in wt glumeruli are indicated. k, Narrow glomerular capillary lumen (L) and thick basement membranes (red arrows) in corin ko and ko/Tg mice at E18.5 shown by electron microscopy.
Figure 2
Figure 2. Impaired trophoblast invasion and spiral artery remodeling in corin ko and ko/Tg mice
E12.5 embryo sections were stained for trophoblasts (a) or smooth muscles (b). Fetal (F) and maternal (M) sides are indicated. Boxed areas in top panels are shown at a higher magnification (x200). c, E18.5 embryo sections were stained for trophoblasts. In lower panels (x100), yellow lines indicate the decidua and myometrium boundary. d, Quantitative data (mean ± s.d.) of cytok staining. e, Fewer and smaller decidual spiral arteries (arrows) in H&E-stained E18.5 corin ko and ko/Tg embryos. f-h, Co-staining of SMA, vWF, cytok and nuclei in E18.5 embryos. Red arrows indicate cytok (green) signals, white arrows vWF (red) signals, and orange arrows mixed (yellow) signals.
Figure 3
Figure 3. Hypertension, proteinuria and uteroplacental pathology in pregnant ANP ko mice
a, BP (mean ± s.d.) in np females, **P<0.01. b, Elevated BP (mean ± s.d.) in pregnant ANP ko mice. †P<0.05 vs. np level. c, Gestational proteinuria in ANP ko mice. Data represent mean ± s.d. Impaired trophoblast invasion and smooch muscle remodeling in E12.5 embryos stained for cytok (d) or SMA (e). Boxed areas in top panels are shown at a higher magnification (x200). f, Impaired trophoblast invasion in E18.5 embryos stained for cytok. g, Quantitative data (mean ± s.d.) of cytok staining in E18.5 ANP ko embryos. h, Impaired decidual and myometrial artery remodeling (arrows) in H&E-stained E18.5 ANP ko embryos. i, Co-staining of cytok, vWF and nuclei in E18.5 ANP ko embryos. Red arrows indicate cytok (green) signals and white arrows vWF (red) signals.
Figure 4
Figure 4. ANP-stimulated human trophoblast invasion, and impaired uterine corin expression and corin mutations in preeclamptic patients
a, A model illustrating that corin-produced ANP in the pregnant uterus promotes trophoblast invasion (red arrows) and vascular wall remodeling (black arrows). ANP stimulated human BeWo and primary trophoblasts in Matrigel invasion (b) and intracellular cGMP production (c). Data represent mean ± s.d. *P<0.05; **P<0.01 vs. control. Corin mRNA (d) and protein (e) and N-terminal (NT) pro-ANP levels (f) in human uterus samples. Horizontal lines indicate mean values. g, Plasma soluble corin levels (mean ± s.d.) in preeclamptic patients and normal controls. h-j, CORIN gene mutations causing K317E (h) and S472G (i) changes in corin (j). TM, transmembrane; Fz, frizzled; LDLR, LDL receptor; SR, scavenger receptor. k,l, Expression of K317E and S472G mutants in HEK293 cells (top panels). Vector, wt corin and inactive corin R801A and S985A mutants were controls. K317E and S472G mutations reduced pro-ANP processing activity (bottom panels). m,n, Quantitative data (mean ± s.d.) from ≥3 experiments.

References

    1. Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta. 2006;27:939–58. - PubMed
    1. Red-Horse K, et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest. 2004;114:744–54. - PMC - PubMed
    1. Wu Q, Xu-Cai YO, Chen S, Wang W. Corin: new insights into the natriuretic peptide system. Kidney Int. 2009;75:142–6. - PMC - PubMed
    1. 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. 1999;274:14926–35. - PubMed
    1. Lain KY, Roberts JM. Contemporary concepts of the pathogenesis and management of preeclampsia. Jama. 2002;287:3183–6. - PubMed

Publication types

MeSH terms