Lysophosphatidic Acid Up-Regulates Vascular Endothelial Growth factor-C and Lymphatic Marker Expressions in Human Endothelial Cells

Cell Mol Life Sci. 2008 Sep;65(17):2740-51. doi: 10.1007/s00018-008-8314-9.

Abstract

Lysophosphatidic acid (LPA) is a low-molecular-weight lipid growth factor, which binds to G-protein-coupled receptors. Previous studies have shown that LPA enhances vascular endothelial growth factor-A (VEGF-A) expression in cancer cells and promotes angiogenesis process. However, the roles of LPA in lymphatic vessel formation and lymphangiogenesis have not been investigated. Here, we demonstrated that LPA up-regulated VEGF-C mRNA and protein expressions in human umbilical vein endothelial cells (HUVECs). Furthermore, the expression levels of lymphatic markers, including Prox-1, LYVE-1 and podoplanin, were enhanced in LPA-stimulated tube forming endothelial cells in vitro and in vivo. Moreover, we showed that pretreatment with MAZ51, a VEGFR-3 kinase inhibitor, and introduction of VEGFR-3 siRNA suppressed LPA-induced HUVEC tube formation and lymphatic marker expressions. These results demonstrated that LPA enhances expression of lymphatic markers through activating VEGF-C receptors in endothelial cells. This study provides basic information that LPA might be a target for therapeutics against lymphangiogenesis and tumor metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Indoles / pharmacology
  • Lymphocytes / drug effects*
  • Lymphocytes / metabolism*
  • Lysophospholipids / pharmacology*
  • Membrane Glycoproteins / genetics
  • Naphthalenes / pharmacology
  • RNA, Messenger / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation / drug effects*
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vesicular Transport Proteins / genetics

Substances

  • 3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one
  • Biomarkers
  • Homeodomain Proteins
  • Indoles
  • LYVE1 protein, human
  • Lysophospholipids
  • Membrane Glycoproteins
  • Naphthalenes
  • PDPN protein, human
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor C
  • Vesicular Transport Proteins
  • prospero-related homeobox 1 protein
  • lysophosphatidic acid