YC-1 reduces placental sFlt-1 and soluble endoglin production and decreases endothelial dysfunction: A possible therapeutic for preeclampsia.

Abstract

Preeclampsia is a serious complication of pregnancy with no medical treatment. It is caused by intermittent placental hypoxia and release of sFlt-1 and soluble endoglin, leading to wide spread maternal endothelial dysfunction and multisystem organ injury. YC-1 is a guanylyl cyclase activator and HIF1α inhibitor developed for use in hypertension and atherosclerosis. We examined whether YC-1 reduces sFlt-1 and sENG secretion and reverses endothelial dysfunction in primary human tissues. YC-1 significantly reduced sFlt-1 and sENG secretion from human umbilical vein endothelial cells, purified primary trophoblast cells and placental explants taken from patients with preterm preeclampsia. This was concordant with reduced HIF1α expression. YC-1 also reversed TNFα induced endothelial dysfunction, including reduced vascular cell adhesion molecule 1 expression and monocyte adhesion to primary endothelial cells. We conclude YC-1 decreases placental production of sFlt-1 and sENG and decreases endothelial dysfunction. It is a novel therapeutic candidate for preeclampsia.

• Authors: Fiona C Brownfoot, Stephen Tong, Natalie J Hannan, Roxanne Hastie, Ping Cannon, Laura Tuohey, Tu'uhevaha J Kaitu'u-Lino
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 413 Pg. 202-8 (Sep 15 2015) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 26159901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antigens, CD
• ENG protein, human
• Endoglin
• Indazoles
• Pregnancy Proteins
• Receptors, Cell Surface
• 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adult
• Antigens, CD
• Endoglin
• Female
• Human Umbilical Vein Endothelial Cells (metabolism, pathology)
• Humans
• Indazoles (pharmacology)
• Placenta (metabolism)
• Pre-Eclampsia (drug therapy, metabolism, pathology)
• Pregnancy
• Pregnancy Proteins (biosynthesis)
• Receptors, Cell Surface
• Vascular Endothelial Growth Factor Receptor-1 (biosynthesis)