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

Abstract

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.

Quantifying trophoblast migration: In vitro approaches to address in vivo situations

“…For example, the ability to generate murine gene knockout or overexpression models allows us to distinguish how specific genes may contribute to trophoblast invasion. 4,5 More recently the rat has gained favor as a model of trophoblast invasion as it confers several advantages over the mouse in that the depth of trophoblast invasion follows a similar pattern to that observed in the human and trophoblasts also colonize the spiral arteries and contribute to their remodeling. [6][7][8] Finally, animal models allow the complex in vivo interactions between the trophoblast and endometrium to be examined, an aspect of trophoblast invasion that is particularly difficult to accurately replicate in vitro.…”

New Developments in the Pathogenesis of Preeclampsia

“…In preeclampsia, this process does not occur appropriately, and therefore invasion into the spiral arteries is incomplete. Various pathways including deficient heme oxygenase expression, genetic factors, oxidative stress, immune factors such as angiotensin receptor autoantibodies or altered natural killer cell signaling and, more recently deficient catechol-O-methyl transferase or deficient corin enzymes have been all proposed to have key roles in inducing placental disease [10][11][12][13][14][15] . However it is not known whether any one of more of these pathways play a casual role in mediating the abnormal placentation noted in humans with preeclampsia.…”

Heart Failure

“…In view of these findings 11 and the intriguing possibility that corin deficiency may be implicated in other disturbances of vascular constrictor tone such as preeclampsia, 12 modulation of corin expression and activity becomes an attractive therapeutic target.…”