Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through Flk-1/KDR activation of c-Src

Han He, Virginia J. Venema, Xiaolin Gu, Richard C Venema, Mario B Marrero, Ruth B Caldwell

Research output: Contribution to journalArticle

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Abstract

Vascular endothelial growth factor (VEGF) is a potent endothelial cell- specific mitogen that promotes angiogenesis, vascular hyperpermeability, and vasodilation by autocrine mechanisms involving nitric oxide (NO) and prostacyclin (PGI2) production. These experiments used immunoprecipitation and immunoassay procedures to characterize the signaling pathways by which VEGF induces NO and PGI2 formation in cultured endothelial cells. The data showed that VEGF stimulates complex formation of the flk-1/kinase-insert domain-containing receptor (KDR) VEGF receptor with c-Src and that Src activation is required for VEGF induction of phospholipase C γ1 activation and inositol 1,4,5-trisphosphate formation. Reporter cell assays showed that VEGF promotes a ~50-fold increase in NO formation, which peaks at 5-20 min. This effect is mediated by a signaling cascade initiated by flk-1/KDR activation of c-Src, leading to phospholipase C γ1 activation, inositol 1,4,5-trisphosphate formation, release of [Ca2+](i) and nitric oxide synthase activation. Immunoassays of VEGF-induced 6-keto prostaglandin F(1α) formation as an indicator of PGI2 production revealed a 3-4-fold increase that peaked at 45-60 min. The PGI2 signaling pathway follows the NO pathway through release of [Ca2+](i), but diverges prior to NOS activation and also requires activation of mitogen-activated protein kinase. These results suggest that NO and PGI2 function in parallel in mediating the effects of VEGF.

Original languageEnglish (US)
Pages (from-to)25130-25135
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number35
DOIs
StatePublished - Aug 27 1999

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Vascular Endothelial Growth Factor Receptor-2
Endothelial cells
Epoprostenol
Vascular Endothelial Growth Factor A
Nitric Oxide
Phosphotransferases
Endothelial Cells
Chemical activation
Inositol 1,4,5-Trisphosphate
Type C Phospholipases
Immunoassay
Vascular Endothelial Growth Factor Receptor
Prostaglandins F
Mitogen-Activated Protein Kinases
Mitogens
Immunoprecipitation
Vasodilation
Nitric Oxide Synthase
Blood Vessels
Cultured Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through Flk-1/KDR activation of c-Src. / He, Han; Venema, Virginia J.; Gu, Xiaolin; Venema, Richard C; Marrero, Mario B; Caldwell, Ruth B.

In: Journal of Biological Chemistry, Vol. 274, No. 35, 27.08.1999, p. 25130-25135.

Research output: Contribution to journalArticle

He, Han ; Venema, Virginia J. ; Gu, Xiaolin ; Venema, Richard C ; Marrero, Mario B ; Caldwell, Ruth B. / Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through Flk-1/KDR activation of c-Src. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 35. pp. 25130-25135.
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