Summary In pregnancy, trophoblast invasion and uterine spiral artery remodeling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodeling has long been implicated in preeclampsia, a major complication of pregnancy, but the underlying mechanisms remain unclear1, 2. Corin is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone important in regulating blood pressure3. Unexpectedly, corin expression was detected in the pregnant uterus4. Here we identify a novel function of corin and ANP in promoting trophoblast invasion and spiral artery remodeling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of preeclampsia. In these mice, trophoblast invasion and uterine spiral artery remodeling were markedly impaired. Consistently, we find that ANP potently stimulated human trophoblasts in invading Matrigels. In patients with preeclampsia, uterine corin mRNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified corin gene mutations in preeclamptic 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 preeclampsia.

Corin is a cardiac membrane protease that activates natriuretic peptides. It is unknown how corin function is regulated. Recently, soluble corin was detected in human plasma, suggesting that corin may be shed from cardiomyocytes. Here we examined soluble corin production and activity and determined the proteolytic enzymes responsible for corin cleavage. We expressed human corin in HEK 293 cells and detected three soluble fragments of ϳ180, ϳ160, and ϳ100 kDa, respectively, in the cultured medium by Western blot analysis. All three fragments were derived from activated corin molecules. Similar results were obtained in HL-1 cardiomyocytes. Using protease inhibitors, ionomycin and phorbol myristate acetate stimulation, small interfering RNA knockdown, and site-directed mutagenesis, we found that ADAM10 was primarily responsible for shedding corin in its juxtamembrane region to release the ϳ180-kDa fragment, corresponding to the near-entire extracellular region. In contrast, the ϳ160-and ϳ100-kDa fragments were from corin autocleavage at Arg-164 in frizzled 1 domain and Arg-427 in LDL receptor 5 domain, respectively. In functional studies, the ϳ180-kDa fragment activated atrial natriuretic peptide, whereas the ϳ160-and ϳ100-kDa fragments did not. Our data indicate that ADAM-mediated shedding and corin autocleavage are important mechanisms regulating corin function and preventing excessive, potentially hazardous, proteolytic activities in the heart. Natriuretic peptides act as a cardiac endocrine mechanism to regulate blood volume and pressure (1, 2). Corin is a serine protease that activates atrial natriuretic peptides (ANP) 2 and B-type natriuretic peptides in the heart (3, 4). The physiological importance of corin function has been shown in mouse models, in which disruption of the corin gene causes hypertension and cardiac hypertrophy (5, 6). In humans, population studies have identified polymorphisms (T555I/Q568P) in the corin gene in African Americans who had high blood pressure and cardiac hypertrophy (7-9). The polymorphisms were shown to alter corin protein structure and impair its biological activity in functional studies (10). In patients with heart failure (HF), the corin variants were associated with poor natriuretic peptide processing and worse clinical outcomes (11).Corin belongs to the type II transmembrane serine protease family, a subclass of trypsin-like enzymes defined by an N-terminal transmembrane domain and a C-terminal protease domain (12, 13). The transmembrane domain anchors the proteases on the cell surface, localizing the biological activities at specific sites. Under physiological and/or pathological conditions, type II transmembrane serine proteases can be shed from the cell surface. Soluble forms of enteropeptidase, hepsin and matriptases, for example, have been reported (14 -17). Recently, soluble corin was detected in human blood, indicating that corin is shed from the heart (18 -20). Interestingly, plasma corin levels were lower in patients with severe HF compared with those of normal...

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