Preeclampsia is a hypertensive complication of pregnancy that affects 3 to 5% of pregnant women and remains associated with substantial maternal and fetal morbidity and mortality. Despite extensive research, its etiopathogenic mechanisms remain poorly understood. It is now accepted that early defective placentation, marked by insufficient vascular remodeling and impaired invasion of the myometrium by extravillous trophoblast cells, leads to placental dysfunction associated with hypoxia and reoxygenation phenomena. This dysfunction triggers the release of various factors into the maternal circulation, which are responsible for the endothelial damage that characterizes the disease.
In this context, the authors focused on CORIN, a type II transmembrane serine protease primarily expressed in cardiomyocytes, where it converts the pro-atrial natriuretic peptide into its active form, a cardiac hormone involved in the regulation of cardiac function and blood pressure. Elevated levels of soluble CORIN had been reported in preeclampsia, with the assumption of a cardiac origin. The hypothesis explored here is different: the soluble form would be released during pregnancy by the syncytiotrophoblast, and its increase in preeclampsia would originate from the placenta. To test this, plasma levels of soluble CORIN were measured by enzyme-linked immunosorbent assay in 375 patients (181 cases of preeclampsia and 194 controls), while the expression and secretion of the protein were analyzed in primary villous cytotrophoblasts differentiated in vitro and in placental explants, using quantitative RT-PCR, Western blot, and immunohistochemistry.
The results confirm significantly higher plasma levels of soluble CORIN in preeclamptic patients than in controls, in both early- and late-onset forms. Cellular analysis shows that CORIN is expressed and secreted by trophoblast cells, particularly by the syncytiotrophoblast: mRNA expression is higher there than in villous cytotrophoblasts, and only the cleaved form of the protein, of approximately 60 kDa, is secreted. Finally, placental tissues and explants from preeclamptic pregnancies produce and secrete significantly more CORIN than those from uncomplicated pregnancies.
This study is the first to demonstrate that CORIN is secreted by the syncytiotrophoblast and that the increase in soluble CORIN in preeclampsia is of placental origin. As these cells are in direct contact with maternal blood, the placenta emerges as a new source of circulating soluble CORIN. Like other markers of the disease, this increase would reflect placental dysfunction. The authors emphasize, however, that the possible mechanistic role of soluble CORIN remains to be elucidated: its increase could correspond to a compensatory mechanism, or else make soluble CORIN merely a marker of placental dysfunction without a direct role in the pathology.