Lysophosphatidic acid up-regulates vascular endothelial growth factor-C and lymphatic marker expressions in human endothelial cells.
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.
Lin
C-I
CI
Institute of Zoology, National Taiwan University, 1 Roosevelt Rd., Sec. 4, Taipei 106, Taiwan.
Chen
C-N
CN
Huang
M-T
MT
Lee
S-J
SJ
Lin
C-H
CH
Chang
C-C
CC
Lee
H
H
D015415:Biomarkers; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein; D000098853:Podoplanin
D015415:Biomarkers; D018398:Homeodomain Proteins; D007211:Indoles; D008246:Lysophospholipids; D008562:Membrane Glycoproteins; D009281:Naphthalenes; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C441602:3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one; C119248:LYVE1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin; C032881:lysophosphatidic acid