Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice

Brian L. Harry, John M. Sanders, Ryan E. Feaver, Melissa Lansey, Tracy L. Deem, Alexander Zarbock, Anthony C. Bruce, Andrew W. Pryor, Bradley D. Gelfand, Brett R. Blackman, Martin A. Schwartz, Klaus Ley

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

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-κB 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-κB 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-κB-mediated gene expression.

Original languageEnglish (US)
Pages (from-to)2003-2008
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume28
Issue number11
DOIs
StatePublished - Nov 2008
Externally publishedYes

Keywords

  • Adhesion molecules
  • Atherosclerosis
  • Endothelium
  • Macrophages
  • Shear stress sensing

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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