Faculty Collaboration Database

Peroxynitrite reduces the endothelium-derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knockout mice. Am J Physiol Regul Integr Comp Physiol 2006 Jan;290(1):R57-65

Date

09/17/2005

Pubmed ID

16166207

DOI

10.1152/ajpregu.00424.2005

Scopus ID

2-s2.0-33644840773 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

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(omega)-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.

Author List

Liu Y, Bubolz AH, Shi Y, Newman PJ, Newman DK, Gutterman DD

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Azoles
Biological Factors
Coronary Vessels
Gene Deletion
Hydrogen Peroxide
Indomethacin
Isoindoles
Male
Mice
Mice, Knockout
NG-Nitroarginine Methyl Ester
Nitric Oxide
Organoselenium Compounds
Peroxynitrous Acid
Platelet Endothelial Cell Adhesion Molecule-1
Prostaglandins
Tyrosine
Vasodilation