Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells

PLoS One. 2016 Feb 10;11(2):e0148968. doi: 10.1371/journal.pone.0148968. eCollection 2016.

Abstract

The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL), a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF) signaling and angiogenesis in endothelial cells (ECs). We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day) recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology*
  • Animals
  • Antigens, CD / metabolism
  • Cadherins / metabolism
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Hindlimb / blood supply
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / physiology*
  • Humans
  • Ischemia / physiopathology
  • Lactones / pharmacology*
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic
  • Protein Transport / drug effects
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inducing Agents
  • Antigens, CD
  • Cadherins
  • Lactones
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • acetylbritannilatone
  • cadherin 5
  • Vascular Endothelial Growth Factor Receptor-2

Grants and funding

This project was supported by the National Natural Science Foundation of China (No. 31271466 and 31571176) and Hebei Province Science and Technique Supporting Project (No.13277739D). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.