Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells

Andreas Papapetropoulos, Guillermo García-Cardeña, Joseph A. Madri, William C. Sessa

Research output: Contribution to journalArticle

948 Scopus citations

Abstract

Vascular endothelial growth factor (VEGF) is a regulator of vascalogenesis and angiogenesis. To investigate the role of nitric oxide (NO) in VEGF-induced proliferation and in vitro angiogenesis, human umbilical vein endothelial cells (HUVEC) were used. VEGF stimulated the growth of HUVEC in an NO-dependent manner. In addition, VEGF promoted the NO-dependent formation of network-like structures in HUVEC cultured in three dimensional (3D) collagen gels. Exposure of cells to VEGF led to a concentration-dependent increase in cGMP levels, an indicator of NO production, that was inhibited by nitro-L-arginine methyl ester. VEGF-stimulated NO production required activation of tyrosine kinases and increases in intracellular calcium, since tyrosine kinase inhibitors and calcium chelators attenuated VEGF-induced NO release. Moreover, two chemically distinct phosphoinositide 3 kinase (PI-3K) inhibitors attenuated NO release after VEGF stimulation. In addition, HUVEC incubated with VEGF for 24 h showed an increase in the amount of endothelial NO synthase (eNOS) protein and the release of NO. In summary, both short- and long-term exposure of human EC to VEGF stimulates the release of biologically active NO. While long-term exposure increases eNOS protein levels, short- term stimulation with VEGF promotes NO release through mechanisms involving tyrosine and PI-3K kinases, suggesting that NO mediates aspects of VEGF signaling required for EC proliferation and organization in vitro.

Original languageEnglish (US)
Pages (from-to)3131-3139
Number of pages9
JournalJournal of Clinical Investigation
Volume100
Issue number12
DOIs
StatePublished - Dec 15 1997
Externally publishedYes

Keywords

  • Angiogenesis
  • CGMP
  • Endothelium
  • Nitric oxide
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Medicine(all)

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