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Getting at the Heart of Pre-eclampsia

Heart development genes implicated in hypertension in pregnancy

by Kimberly McGhee

Downton Abbey fans were shocked when, shortly after giving birth, beloved Lady Sybil suddenly fell into violent seizures and died. Few fans had heard of eclampsia, the most severe form of pre-eclampsia (PE), which can lead to liver and kidney failure, stroke and seizure, bleeding disorders, and death. Although PE is usually successfully treated before progression to eclampsia in the U.S., it remains the leading cause of preterm birth and can increase a woman’s lifetime risk for cardiovascular disease. The hallmark symptoms of PE—aggressive hypertension and protein in the urine—are likely due to leaky or stunted blood vessels.

A surprise finding by Kyu-Ho Lee, M.D., Ph.D., of MUSC’s Department of Pediatrics may shed light on the chain of events that sets this potentially deadly disease in motion. That finding, and the exciting line of research that has grown from it, would not have been possible without close collaboration between researchers and clinicians at MUSC Children’s Hospital.

Lee, who studies the role of the gene Nkx2-5 in embryonic heart development, knew that abnormal placentae and amniotic blood vessels were also seen in Nkx2-5 mutant mice. When he learned of a study of women with early-onset or severe PE by neonatologist Carol L. Wagner, M.D., and Obstetrics & Gynecology Chair Donna D. Johnson, M.D., curiosity led him to test the placental samples they had collected for Nkx2-5 expression.

To his amazement, he found a correlation between very high levels of Nkx2-5 expression in specialized placental cells known as trophoblasts and high levels of sFlt1, an emerging PE biomarker, in some PE patients.

“We were very excited by this completely unexpected link between fetal heart development and a highly significant disease of pregnancy,” says Lee. This excitement led to a fruitful collaboration with Johnson and maternal fetal medicine specialists Eugene Y. Chang, M.D., and Roger B. Newman, M.D., Vice Chair of Women’s Health Research.

sFlt1 is produced by alternative messenger RNA splicing of the vascular endothelial growth factor (VEGF) type 1 receptor (VEGFR1), which relays signals promoting blood vessel growth. Like VEGFR1, sFlt1 can bind VEGF in the circulation, but because it thus competes with VEGFR1 signaling, it antagonizes blood vessel growth as a part of a normal balancing mechanism. Disproportionately high sFlt1 levels during pregnancy are associated with abnormal blood vessel development and the onset of PE symptoms.

Recalling from his cardiac research that Sam68, an RNA splicing factor, was activated downstream of Nkx2-5 expression in heart development, Lee also found elevated Sam68 levels in the PE samples that correlated with Nkx2-5 and sFlt1 expression levels. When Sam68 expression was depleted in cell models using RNA interference, alternative splicing of VEGFR1 produced less sFlt1 RNA.1

“We think that Sam68 is the lever regulating sFlt1 production and that Nkx2-5 is pressing on that lever in some PE patients,” says Lee.

To prove this hypothesis, Lee is monitoring sFlt1 and Sam68 levels in an animal model overexpressing Nkx2-5 in the placenta and is looking for other harbingers of PE, with the hope that the Nkx2-5 pathway could be targeted to find future treatments for PE.

References

1 Rivers ER, Horton AL, Hawk AF, Favre EG, Senf KM, Nietert PJ, Chang EY, Foley AC, Robinson CJ, Lee KH. Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia. Hypertens Pregnancy 2014 Nov;33(4):412-426.

Above: Human embryo at 7-8 weeks old. Image by Dr. G. Moscoso. Licensed from sciencesource.com.