Serine Protease Corin in Pregnancy-induced Hypertension

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DESCRIPTION (provided by applicant): Pregnancy-induced hypertension increases maternal and neonatal morbidity and mortality, but the underlying cause is poorly understood. Corin is a newly-discovered protease. It converts pro-atrial natriuretic peptide (pro-ANP) to active ANP, a cardiac hormone that regulates blood pressure. Corin knockout mice develop hypertension, indicating the importance of corin in maintaining normal blood pressure. In humans, corin variants are associated with an increased risk for hypertension and cardiac hypertrophy in African Americans. Unexpectedly, we found high levels of corin expression in the pregnant uterus and placenta in mice, suggesting a potential role of corin in pregnancy. We showed that blood pressure increased in pregnant corin null mice but returned to pre-pregnancy levels after delivery. The mice also had late gestational proteinuria, a phenotype reminiscent of preeclampsia in humans. Thus, corin may play an important role in the uterus to prevent hypertension during pregnancy and corin deficiency may contribute to pregnancy-induced hypertension. In this study, we will test this hypothesis in mouse models. In Aim 1, we plan to determine the role of uterine corin in preventing pregnancy-induced hypertension. In Aim 2, we plan to determine the role of uterine ANP production in preventing pregnancy-induced hypertension. In Aim 3, we plan to determine the role of uterine corin-mediated ANP production in regulating spiral artery remodeling. The results from our studies may provide new insights into the pathogenesis of pregnancy-induced hypertension. If our hypothesis is validated, strategies to enhance the corin-mediated pathway may be developed to treat patients with preeclampsia. PUBLIC HEALTH RELEVANCE: High blood pressure, or hypertension, during pregnancy poses a great danger to both the mother and the fetus. The disease happens in ~10% all pregnancies, but the exact cause is not known. Recently, we discovered a new molecule, corin, from the heart that keeps normal blood pressure. In mice lacking corin, blood pressure increased during pregnancy. The pregnant mice also had high protein contents in the urine, a condition similar to patients with pregnancy-induced hypertension. Our results indicate that corin is important in preventing high blood pressure during pregnancy. In this study, we will try to understand how corin works and if we can develop new corin-based methods to diagnose and treat high blood pressure during pregnancy. 1