Resveratrol inhibits release of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin and improves vascular dysfunction - implications as a preeclampsia treatment

Sci Rep. 2017 May 12;7(1):1819. doi: 10.1038/s41598-017-01993-w.

Abstract

Preeclampsia is a disease of pregnancy associated with placental oxidative stress, inflammation and elevated release of anti-angiogenic factors sFlt-1 and soluble endoglin. These placental factors cause generalized maternal endothelial dysfunction. There are no treatments to halt disease progression; delivery is the only cure. Resveratrol modulates pathways involved in inflammation and oxidative stress and may offer a potential therapeutic for preeclampsia. Resveratrol reduced sFlt-1, sFlt-1 e15a and soluble endoglin secretion from primary trophoblasts and HUVECs and reduced mRNA expression of pro-inflammatory molecules NFκB, IL-6 and IL-1β in trophoblasts. IL-6, IL-1β and TNFα secretion were also significantly reduced. In HUVECs, resveratrol significantly increased mRNA of anti-oxidant enzymes HO-1, NQO1, GCLC and TXN but did not significantly alter HO-1 protein expression, whilst reducing HO-1 protein in trophoblast. Endothelial dysfunction was induced in HUVECs using TNFα, increasing expression of cell adhesion molecule VCAM1 and adhesion of peripheral blood mononuclear cells, both of which were increased further by resveratrol. In contrast, resveratrol significantly reduced TNFα-induced Endothelin-1 (a vasoconstrictor) and significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS). In summary, resveratrol decreases secretion of anti-angiogenic factors however its effects on the endothelium are mixed. Overall, it may have potential as a treatment for preeclampsia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Biomarkers
  • Blood Vessels / drug effects*
  • Blood Vessels / metabolism*
  • Cell Survival / drug effects
  • Cytokines / metabolism
  • Endoglin / antagonists & inhibitors*
  • Endoglin / biosynthesis*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Female
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress / drug effects
  • Pre-Eclampsia / drug therapy
  • Pre-Eclampsia / etiology
  • Pre-Eclampsia / metabolism
  • Pregnancy
  • Resveratrol / pharmacology*
  • Resveratrol / therapeutic use
  • Trophoblasts / drug effects
  • Trophoblasts / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-1 / biosynthesis*

Substances

  • Antioxidants
  • Biomarkers
  • Cytokines
  • Endoglin
  • Inflammation Mediators
  • Nitric Oxide Synthase Type III
  • Heme Oxygenase-1
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • Resveratrol