Mechanisms for enhanced endothelium-derived hyperpolarizing factor-mediated responses in microvessels in mice

Junko Ohashi, Ayuko Sawada, Sota Nakajima, Kazuki Noda, Aya Takaki, Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


Background: Endothelium-derived relaxing factors play an important role in cardiovascular homeostasis. Among them, endothelium-derived hyperpolarizing factor (EDHF) is important especially in microcirculation. It has previously been demonstrated that endothelium-derived hydrogen peroxide (H 2O 2) is an EDHF in animals and humans and that endothelial nitric oxide synthase (eNOS) plays diverse roles as a nitric oxide (NO) generating system in conduit arteries and as an EDHF/H 2O 2 generating system in microvessels. As compared with NO-mediated responses, those by EDHF are resistant to atherosclerosis, contributing to the maintenance of cardiovascular homeostasis. The aim of this study is to elucidate the molecular mechanisms for enhanced EDHF-mediated responses in microvessels. Methods and Results: This study used male wild-type mice and caveolin-1-deficient mice (caveolin-1-/- mice). In the endothelium, eNOS was functionally suppressed in mesenteric arteries (microvessels) compared with the aorta (conduit arteries), for which Ca 2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) and caveolin-1 are involved, as EDHF-mediated responses were inhibited by STO-609 (an inhibitor of CaMKKβ) and in caveolin-1-/- mice, respectively. In vascular smooth muscle, relaxation responses to H 2O 2 were enhanced through a protein kinase G1α (PKG1α)-mediated mechanism in mesenteric arteries compared with the aorta, as they were inhibited by Rp-8-BrcGMPS (an inhibitor of PKG1α). Conclusions: These results indicate that CaMKKβ, caveolin-1, and PKG1α are substantially involved in the mechanisms for the enhanced EDHF-mediated responses in microvessels in mice.

Original languageEnglish
Pages (from-to)1768-1779
Number of pages12
JournalCirculation Journal
Issue number7
Publication statusPublished - 2012


  • Endothelial nitric oxide synthase
  • Endothelium-derived hyperpolarizing factor
  • Microveesels
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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