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

Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):2003-8. doi: 10.1161/ATVBAHA.108.164707. Epub 2008 Aug 7.

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-kappaB 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-kappaB activity and VCAM-1 expression under conditions of atheroprone flow.

Conclusions: These results indicate that endothelial PECAM-1 contributes to atherosclerotic lesion formation in regions of disturbed flow by regulating NF-kappaB-mediated gene expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Abdominal / metabolism
  • Aorta, Abdominal / pathology
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Transplantation
  • Cells, Cultured
  • Dietary Fats
  • Disease Models, Animal
  • Disease Progression
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Regional Blood Flow
  • Stress, Mechanical
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Apolipoproteins E
  • Dietary Fats
  • NF-kappa B
  • Platelet Endothelial Cell Adhesion Molecule-1
  • RNA, Small Interfering
  • Vascular Cell Adhesion Molecule-1