Preeclampsia is a serious complication of pregnancy which is associated with poor placental invasion and significant maternal endothelial dysfunction. Growth Differentiation Factor-15 (GDF15) is a stress-response protein which has been considered as a biomarker for cardiovascular disease. We have shown that GDF15 is increased in the maternal circulation in women destined to develop preeclampsia.
This study aimed to assess GDF15 in the placentas of women with established preeclampsia and to undertake functional studies to assess its potential contribution to disease pathogenesis.
Immunofluorescence revealed that GDF15 is localised to the syncytiotrophoblast, or surface of the placenta. In a cohort of placentas collected from women who developed early onset preeclampsia at <34 weeks’ gestation (n=67), GDF15 mRNA expression was significantly increased relative to preterm control placentas (n=18). Given GDF15 is elevated in the circulation of women preceding preeclampsia diagnosis and also increased in cardiovascular disease, we wondered whether placental secretion of GFD15 might contribute to endothelial dysfunction. In our preliminary studies (n=3 separate placental isolations), when we silenced trophoblast GDF15 using siRNA and then exposed endothelial cells to the media (or control media from trophoblast treated with scrambled siRNA), we saw no changes in markers of endothelial dysfunction, Endothelin-1 or Vascular Cell Adhesion Molecule 1. Drug treatments (esomeprazole, metformin or sulfasalazine) that we have previously shown reduce placental secretion of the anti-angiogenic factors of preeclampsia sFlt1 and soluble endoglin did not significantly alter GDF15 secretion.
In conclusion, GDF15 is elevated in preeclamptic placenta and elevated in the circulation of women preceding their diagnosis of preeclampsia. Our endothelial experiments suggest elevated GDF15 is unlikely to contribute to the endothelial dysfunction characteristic of preeclampsia and we have been unable to identify any potential therapeutics that alter its secretion. Further study is required to better understand how and why GDF15 is elevated in preeclampsia.