Vascular endothelial growth factor regulates stanniocalcin-1 expression via neuropilin-1-dependent regulation of KDR and synergism with fibroblast growth factor-2

Cell Signal. 2008 Mar;20(3):569-79. doi: 10.1016/j.cellsig.2007.11.009. Epub 2007 Nov 26.

Abstract

Stanniocalcin-1 (STC-1) is a glycoprotein hormone originally identified as a regulator of calcium and phosphate homeostasis in bony fish. Up-regulation of the mammalian homolog in numerous gene profiling studies of angiogenesis and vascular endothelial growth factor-A (VEGF-A(165))-regulated gene expression, suggests that regulation of this factor may be a key feature of the angiogenic response. Here we investigated the mechanisms mediating VEGF-A(165)-induced STC-1 gene expression in human endothelial cells. VEGF-A(165), acting via VEGFR2/KDR, induced STC-1 through de novo transcription, mediated primarily via intracellular protein kinase C (PKC)- and extracellular signal-regulated protein kinase (ERK)-dependent pathways. VEGF-A(165)-induced STC-1 mRNA expression was synergistically enhanced up to 2-fold by co-treatment with FGF-2, in a mechanism dependent on VEGFR2/KDR and FGFR1. Production of STC-1 protein by endothelial cells was also induced by VEGF-A(165) and synergistically enhanced by co-treatment with FGF-2. Synergism between VEGF-A(165) and FGF-2 was mediated via a novel neuropilin-1 (NP-1)-dependent mechanism, as indicated by the complete inhibition of synergism with either EG3287, a specific neuropilin antagonist, or siRNA-mediated NP-1 knockdown, and by the inability of the VEGF-A(121) isoform to synergise with FGF-2. Surprisingly, we found that NP-1 knockdown also markedly reduced KDR expression in HUVECs, and enhanced the VEGF-A(165)-induced reduction in KDR expression resulting from receptor-mediated endocytosis. These findings support a role for NP-1 in mediating synergistic effects between VEGF-A(165) and FGF-2, which may occur in part through a contribution of NP-1 to KDR stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factor 2 / metabolism*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Humans
  • Neovascularization, Physiologic
  • Neuropilin-1 / antagonists & inhibitors
  • Neuropilin-1 / genetics
  • Neuropilin-1 / metabolism*
  • Peptide Fragments / pharmacology
  • Protein Kinase C / metabolism
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Recombinant Proteins / metabolism
  • Signal Transduction*
  • Time Factors
  • Transcription, Genetic
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Glycoproteins
  • Peptide Fragments
  • RNA, Messenger
  • RNA, Small Interfering
  • Recombinant Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A (138-165)
  • Fibroblast Growth Factor 2
  • Neuropilin-1
  • teleocalcin
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases