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Cardiovascular-Kidney Interactions in Health and Disease

Peroxynitrite reduces the endothelium-derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knockout mice

¹Departments of Medicine, ²Surgery, ³Pharmacology, ⁴Cell Biology, ⁵Microbiology and ⁶Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin; ⁷Veterans Administration Medical Center, Milwaukee, Wisconsin; and ⁸Blood Research Institute of Wisconsin, Milwaukee, Wisconsin

Submitted 15 June 2005 ; accepted in final form 19 August 2005

Platelet endothelial cell adhesion molecule 1 (PECAM-1) is capable of transducing signals in endothelial cells exposed to shear; however, the biological consequences of this signal transduction are unknown. Because shear stress elicits flow-mediated dilation (FMD), we examined whether steady-state FMD in mouse coronary arteries (MCAs) is affected in the PECAM-1 knockout (KO) mouse. MCAs were isolated from wild-type (WT) or KO mice and prepared for videomicroscopy, histofluorescence, Western blotting, and immunohistochemistry. FMD was examined in the absence and presence of N-nitro-L-arginine methyl ester (L-NAME) and L-NAME+indomethacin (INDO). FMD was reduced in KO relative to WT MCAs, but the L-NAME-inhibitable portion of FMD was similar between the two. The INDO-sensitive component of FMD was diminished in KO MCAs. In contrast, the residual component of dilation, presumably because of endothelium-derived hyperpolarizing factor (EDHF), was abolished in KO MCAs. Histofluorescence showed relatively more superoxide (O₂^–·; oxy-ethidium fluorescence) and peroxide production (dihydrochlorofluorescene fluoresecence) in KO MCAs at rest. Flow augmented O₂^–· and peroxide production in WT MCAs but had little effect on KO MCAs. Enhanced nitric oxide generation was observed in arteries from KO mice, accompanied with increased eNOS S1177 phosphorylation. In vessels from KO mice, treatment with ebselen decreased peroxynitrite (ONOO^–) formation and improved the reduced FMD, largely due to restoration of the presumed EDHF component. These results suggest that PECAM-1 is necessary for normal FMD in the mouse coronary circulation. In the absence of this adhesion and signaling molecule, ONOO^– production is increased concomitant with a reduction in both the EDHF and INDO-sensitive components of FMD.

flow-induced dilation; oxidative stress

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