ZFIN ID: ZDB-PUB-050308-1
Thalidomide-induced anti-angiogenic action is mediated by ceramide through depletion of VEGF receptors, and antagonized by sphingosine-1-phosphate
Yabu, T., Tomimoto, H., Taguchi, Y., Yamaoka, S., Igarashi, Y., and Okazaki, T.
Date: 2005
Source: Blood   106(1): 125-134 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Angiogenesis Inhibitors/pharmacology*
  • Animals
  • DNA, Complementary
  • Embryo, Nonmammalian/drug effects
  • Endothelium, Vascular/cytology
  • Eye Abnormalities/chemically induced
  • Humans
  • Lysophospholipids/metabolism*
  • Magnesium/metabolism
  • Neuropilin-1/metabolism
  • Oligonucleotides, Antisense
  • Sphingomyelin Phosphodiesterase/genetics
  • Sphingomyelin Phosphodiesterase/metabolism
  • Sphingosine/analogs & derivatives*
  • Sphingosine/metabolism*
  • Sphingosine/pharmacology
  • Thalidomide/pharmacology*
  • Umbilical Veins/cytology
  • Vascular Endothelial Growth Factor Receptor-2/metabolism*
  • Zebrafish
PubMed: 15741222 Full text @ Blood
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ABSTRACT
Thalidomide, which is clinically recognized as an efficient therapeutic agent for multiple myeloma, has been thought to exert anti-angiogenic action through unknown mechanism. We here show a novel mechanism of thalidomide-induced anti-angiogenesis in zebrafish embryos. Thalidomide induces the defect of major blood vessels, which is demonstrated by their morphological loss and confirmed by the depletion of vascular endothelial growth factor (VEGF) receptors such as neuropilin-1 and Flk-1. Transient increase of ceramide content through activation of neutral sphingomyelinase (nSMase) precedes thalidomide-induced vascular defect in the embryos. Synthetic cell permeable ceramide, N-acetylsphingosine (C2-ceramide) inhibits embryonic angiogenesis as well as thalidomide. The blockade of ceramide generation by anti-sense morpholino oligonucleotides for nSMase prevents thalidomaide-induced ceramide generation and vascular defect. In contrast to ceramide, sphingosine-1-phosphate (S1P) inhibits nSMase-dependent ceramide generation and restores thalidomide-induced embryonic vascular defect with increase of expression of VEGF receptors. In human umbilical vein endothelial cells (HUVECs), thalidomide-induced inhibition of cell growth, generation of ceramide through nSMase and depletion of VEGF receptors are restored to the control levels by pretreatment with S1P. These results suggest that thalidomide-induced anti-angiogenic action is regulated by the balance between ceramide and S1P signal.
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