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1 Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; Pharmacology, Medical College of Wisconsin, Milwaukee, WI, USA; The Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
2 Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; The Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
3 ; Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
4 Pharmacology, Medical College of Wisconsin, Milwaukee, WI, USA; Cell Biology, Medical College of Wisconsin, Milwaukee, WI, USA; The Blood Research Institute of Wisconsin, Milwaukee, WI, USA
5 Microbiology, Medical College of Wisconsin, Milwaukee, WI, USA; The Blood Research Institute of Wisconsin, Milwaukee, WI, USA
6 Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; Pharmacology, Medical College of Wisconsin, Milwaukee, WI, USA; Veterans Administration Medical Center, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: ypliu{at}mcw.edu.
PECAM-1 is capable of transducing signals in endothelial cells exposed to shear; however, the biological consequences of this signal transduction are unknown. Since shear stress elicits flow-mediated dilation (FMD), we examined whether steady-state FMD in mouse coronary arteries (MCA) is affected in the PECAM-1 knock-out (KO) mouse. MCAs were isolated from wild type (WT) or KO mice and prepared for videomicroscopy, histofluorescence, Western blotting, and immuohistochemistry. 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 due to endothelial 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.
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