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

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 1,2 . 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 pressure 3 . Unexpectedly, corin expression was detected in the pregnant uterus 4 . 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 preeclampsia, 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. Pregnancy poses a serious challenge for maintaining normal blood pressure. Pregnancy-induced hypertension, a major cause of maternal and fetal deaths, occurs in approximately 10% of pregnancies 5,6 . During pregnancy, the uterus undergoes profound morphological changes, including trophoblast invasion and spiral artery remodelling. In pre-eclampsia, impaired spiral artery remodelling is common, but the underlying mechanisms are unclear 1,2,7–9 . Studies indicate that vascular growth factor receptors, angiotensin and oestradiol are involved in the disease 10–14 . Corin is a cardiac protease that activates ANP, which is a cardiac hormone that regulates blood pressure and sodium homeostasis 15 .I n mice, lack of CORIN prevents ANP generation and causes hypertension 16 . In humans, CORIN variants are associated with hypertension 17 . Interestingly, Corin expression was detected in the pregnant mouse 4 (Fig. 1A) and human uterus (Supplementary Fig. 1). As a trans