Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF

Alicja Jozkowicz, John P. Cooke, Ibeth Guevara, Ihor Huk, Philip Funovics, Otmar Pachinger, Franz Weidinger, Jozef Dulak

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


Objective: Vascular endothelial growth factor (VEGF) induces the release of nitric oxide (NO) from endothelial cells. There is also limited data suggesting that NO may enhance VEGF generation. Methods: To further investigate this interaction, we examined the effect of exogenous and endogenous NO on the synthesis of VEGF by rat and human vascular smooth muscle cells (VSMC) by exposing cells to exogenous NO donors, or to genetic augmentation of eNOS or iNOS. Results: NO-donors potentiated by 2-fold the generation of VEGF protein by rat or human VSMC. Similarly, rat or human VSMC transiently transfected with plasmid DNA encoding eNOS or iNOS, synthesized up to 3-fold more VEGF than those transfected with control plasmid DNA, an effect which was reversed after treatment with the NOS antagonist L-NAME. Rat VSMC stably transfected with pKeNOS plasmid, constitutively produced NO and released high concentrations of VEGF. In these cells, L-NAME significantly reduced NO synthesis and decreased VEGF generation. The VEGF protein produced by NOS-transfected VSMC was biologically active, as conditioned media harvested from these cells increased endothelial cell proliferation. Conclusion: These studies reveal that NO derived from NO-donors or generated by NOS within the cells, upregulates the synthesis of VEGF in vascular smooth muscle cells. Administration of NO donors, or augmentation of endogenous NO synthesis, may be an alternative approach in therapeutic angiogenesis.

Original languageEnglish (US)
Pages (from-to)773-783
Number of pages11
JournalCardiovascular Research
Issue number4
StatePublished - 2001


  • Endothelial factors
  • Gene expression
  • Growth factors
  • Nitric oxide
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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