Nitric oxide stimulates vascular endothelial growth factor production in cardiomyocytes involved in angiogenesis

Masanori Kuwabara, Yoshihiko Kakinuma, Motonori Ando, Rajesh G. Katare, Fumiyasu Yamasaki, Yoshinori Doi, Takayuki Sato

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


Background: Hypoxia-inducible factor (HIF)-1α regulates the transcription of lines of genes, including vascular endothelial growth factor (VEGF), a major gene responsible for angiogenesis. Several recent studies have demonstrated that a nonhypoxic pathway via nitric oxide (NO) is involved in the activation of HIF-1α. However, there is no direct evidence demonstrating the release of angiogenic factors by cardiomyocytes through the nonhypoxic induction pathway of HIF-1α in the heart. Therefore we assessed the effects of an NO donor, S-Nitroso-N-acetylpenicillamine (SNAP) on the induction of VEGF via HIF-1α under normoxia, using primary cultured rat cardiomyocytes (PRCMs). Methods and Results: PRCMs treated with acetylcholine (ACh) or SNAP exhibited a significant production of NO. SNAP activated the induction of HIF-1α protein expression in PRCMs during normoxia. Phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation was induced by SNAP and was completely blocked by wortmannin, a PI3K inhibitor, and N G-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor. The SNAP treatment also increased VEGF protein expression in PRCMs. Furthermore, conditioned medium derived from SNAP-treated cardiomyocytes phosphorylated the VEGF type-2 receptor (Flk-1) of human umbilical vein endothelial cells (a fourfold increase compared to the control group, p < 0.001, n = 5) and accelerated angiogenesis. Conclusion: Our results suggest that cardiomyocytes produce VEGF through a nonhypoxic HIF-1α induction pathway activated by NO, resulting in angiogenesis.

Original languageEnglish
Pages (from-to)95-101
Number of pages7
JournalJournal of Physiological Sciences
Issue number1
Publication statusPublished - Feb 2006
Externally publishedYes


  • Angiogenesis
  • Cardiomyocyte
  • Flk-1
  • Nitric oxide
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology


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