on August 7, 2008
Published online before print August 7, 2008, doi: 10.1161/ATVBAHA.108.164707
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Submitted on February 8, 2008
Accepted on July 30, 2008
Endothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice
Brian L. Harry ;
From the Robert M. Berne Cardiovascular Research Center (B.L.H., J.M.S., R.E.F., T.L.D., A.Z., A.C.B., A.W.P., B.D.G., B.R.B., M.A.S., K.L.), Departments of Biomedical Engineering (B.L.H., R.E.F., B.D.G., B.R.B., M.A.S., K.L.), Molecular Physiology and Biophysics (M.L., K.L.), and Microbiology (M.A.S.), University of Virginia, Charlottesville; Department of Anesthesiology and Critical Care Medicine (A.Z.), University of Münster, Germany; and the Division of Inflammation Biology (A.Z., K.L.), La Jolla Institute for Allergy & Immunology, La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: klaus{at}liai.org.
Objective—Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) has recently been shown to form an essential element of a mechanosensory complex that mediates endothelial responses to fluid shear stress. The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis.
Methods and Results—We crossed C57BL/6 Pecam1-/- mice with apolipoprotein E–deficient (Apoe-/-) mice. On a Western diet, Pecam1-/-Apoe-/- mice showed reduced atherosclerotic lesion size compared to Apoe-/- mice. Striking differences were observed in the lesser curvature of the aortic arch, an area of disturbed flow, but not in the descending thoracic or abdominal aorta. Vascular cell adhesion molecule-1 (VCAM-1) expression, macrophage infiltration, and endothelial nuclear NF-
B were all reduced in Pecam1-/-Apoe-/- mice. Bone marrow transplantation suggested that endothelial PECAM-1 is the main determinant of atherosclerosis in the aortic arch, but that hematopoietic PECAM-1 promotes lesions in the abdominal aorta. In vitro data show that siRNA-based knockdown of PECAM-1 attenuates endothelial NF-B activity and VCAM-1 expression under conditions of atheroprone flow.
Conclusion—These results indicate that endothelial PECAM-1 contributes to atherosclerotic lesion formation in regions of disturbed flow by regulating NF-B–mediated gene expression.
Key words: atherosclerosis • shear stress sensing • adhesion molecules • endothelium • macrophages
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