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Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1703-10. doi: 10.1161/ATVBAHA.110.209726. Epub 2010 Aug 11.

Endothelium-dependent coronary vasodilatation requires NADPH oxidase-derived reactive oxygen species.

Author information

1
Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass., USA.

Abstract

OBJECTIVE:

To determine the functional significance of physiological reactive oxygen species (ROS) levels in endothelium-dependent nitric oxide (NO)-mediated coronary vasodilatation.

METHODS AND RESULTS:

Endothelium-derived NO is important in regulating coronary vascular tone. Excess ROS have been shown to reduce NO bioavailability, resulting in endothelial dysfunction and coronary diseases. NADPH oxidase is a major source of ROS in endothelial cells (ECs). By using lucigenin-based superoxide production and dichlorfluorescein diacetate (DCFH-DA) fluorescence-activated cell sorter assays, we found that mouse heart ECs from NADPH oxidase-knockdown (p47(phox-/-)) animals have reduced NADPH oxidase activity (>40%) and ROS levels (>30%) compared with wild-type mouse heart ECs. Surprisingly, a reduction in ROS did not improve coronary vasomotion; rather, endothelium-dependent vascular endothelial growth factor-mediated coronary vasodilatation was reduced by greater than 50% in p47(phox-/-) animals. Western blots and L-citrulline assays showed a significant reduction in Akt/protein kinase B (PKB) and endothelial NO synthase phosphorylation and NO synthesis, respectively, in p47(phox-/-) coronary vessels and mouse heart ECs. Adenoviral expression of constitutively active endothelial NO synthase restored vascular endothelial growth factor-mediated coronary vasodilatation in p47(phox-/-) animals.

CONCLUSIONS:

Endothelium-dependent vascular endothelial growth factor regulation of coronary vascular tone may require NADPH oxidase-derived ROS to activate phosphatidylinositol 3-kinase-Akt-endothelial NO synthase axis.

PMID:
20702812
PMCID:
PMC2924465
DOI:
10.1161/ATVBAHA.110.209726
[Indexed for MEDLINE]
Free PMC Article

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