The Role of Corin and ANP in Adverse Pregnancy Outcomes

Groundbreaking research inspires 4th-year medical student’s study

By Uma Perni, MD

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Preeclampsia is a major cause of maternal and neonatal morbidity and mortality worldwide, affecting 5 percent to 8 percent of all pregnancies. It is a leading cause of medically indicated preterm birth. Preterm birth, in turn, is associated with significant health risks to newborns as well as an estimated annual $26 billion cost to the healthcare system.

Preeclampsia is a syndrome in which reduced uteroplacental perfusion is associated with widespread endothelial dysfunction and often fetal growth restriction. Primary clinical features include hypertension, proteinuria, edema and, at times, end-organ dysfunction, including elevated liver enzymes, thrombocytopenia, pulmonary edema and seizures. The primary cause of preeclampsia remains elusive, but impaired trophoblast invasion and spiral artery remodeling are thought to be involved in its pathogenesis.

In normal early pregnancy, trophoblast cells from the developing placenta invade the endometrium and myometrium. They migrate along the spiral arteries, transforming them into large-diameter conduit vessels of low resistance. This physiological transformation allows for greater blood flow to the growing fetus and is required for a successful pregnancy.

Failure of trophoblast invasion and spiral artery transformation has been documented in preeclampsia and in pregnancies complicated by intrauterine growth restriction (IUGR). Thus, failure of the spiral arteries to undergo physiological transformation is a significant finding in adverse pregnancy outcomes.

Despite the importance of trophoblast invasion and vascular remodeling, these processes are still not well understood.

In a study published in Nature in 2012, Cleveland Clinic researcher Qingyu Wu, MD, PhD, reported the discovery of a novel function of corin and atrial natriuretic peptide (ANP) in promoting trophoblast invasion and spiral artery remodeling. Corin is a cardiac protease that activates ANP, a cardiac hormone involved in the complex pathway of blood pressure regulation. Lack of corin in mouse models causes hypertension; in humans, genetic variants of corin are associated with high blood pressure.

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Unexpectedly, corin was also detected in the pregnant uterus, suggesting a possible function in pregnancy. Using transgenic mouse models, cell-based experiments with human trophoblasts and Matrigel™ matrices, as well as the serum of preeclamptic women, Dr. Wu and his team reported the role of corin and ANP in promoting trophoblast invasion and spiral artery remodeling, and in preventing hypertension in pregnancy. The data suggest that impaired corin expression or function in the pregnant uterus may represent an important mechanism underlying preeclampsia.

Genesis of cohort study

Reading the Nature report stimulated Anjalika Gandhi, a fourth-year student at Cleveland Clinic Lerner College of Medicine, to ask how such groundbreaking basic scientific findings could be translated into the clinical realm to help patients. Clinically, a major challenge in the practice of obstetrics is to identify women who will develop preeclampsia. Despite significant research into potential biomarkers, no single marker or group of markers has been able to predict this condition.

Ms. Gandhi, who has worked with Cleveland Clinic’s Ob/Gyn & Women’s Health Institute in other research endeavors, formulated clinical research questions based on Dr. Wu’s findings. Together, we designed a prospective cohort study of high-risk pregnant women to better understand the role of corin and the development of adverse pregnancy outcomes, including preeclampsia and IUGR.

Women with one or more risk factors for developing preeclampsia — including but not limited to chronic hypertension, pregestational diabetes, obesity or a prior history of preeclampsia — are approached for participation. Those who agree to participate have blood collected at two time points in their pregnancy for analysis.

Specifically, we are investigating early pregnancy serum corin and ANP levels in women who develop preeclampsia and/or IUGR, compared with those who do not. We will also include a small cohort of low-risk pregnancies for comparison.

Hypothesis and goals

We hypothesize that in early pregnancy, serum corin and ANP levels will be decreased in women who develop preeclampsia and/or growth restriction secondary to the role of these proteins in early trophoblast invasion.

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We will also investigate changes in these levels in late pregnancy to identify differences between the two groups. We plan to compare early and late levels in women who develop preeclampsia and require preterm delivery to those of women who develop preeclampsia and deliver at term.

Our final question will be whether including corin and ANP as predictive markers improves the predictive capability of other well-studied markers, such as placental growth factor.

Recruitment took place from September 2013 to March 2014, with 133 patients enrolled. Final pregnancy outcomes have been collected, and the data is currently being analyzed. This study is funded by a grant from Cleveland Clinic’s Research Program Committee. Statistical analyses will be aided by Benjamin Nutter from the Lerner College of Medicine Department of Quantitative Health Sciences.

Dr. Perni is an associate staff member of the Department of Obstetrics in Cleveland Clinic’s Ob/Gyn & Women’s Health Institute.