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The role of platelet-endothelial cell adhesion molecule-1 in atheroma formation varies depending on the site-specific hemodynamic environment.

AbstractOBJECTIVE:
Polymorphisms in the platelet-endothelial cell adhesion molecule (PECAM-1)-1 gene are linked to increased risk of coronary artery disease. Because PECAM-1 has been demonstrated to form a mechanosensory complex that can modulate inflammatory responses in murine arterial endothelial cells, we hypothesized that PECAM-1 contributes to atherogenesis in a shear-dependent and site-specific manner.
APPROACH AND RESULTS:
ApoE(-/-) mice that were wild-type, heterozygous, or deficient in PECAM-1 were placed on a high-fat diet. Detailed analysis of the aorta at sites with differing hemodynamics revealed that PECAM-1-deficient mice had reduced disease in areas of disturbed flow, whereas plaque burden was increased in areas of steady, laminar flow. In concordance with these observations, bone marrow chimera experiments revealed that hematopoietic PECAM-1 resulted in accelerated atheroma formation in areas of laminar and disturbed flow, however endothelial PECAM-1 moderated disease progression in areas of high sheer stress. Moreover, using shear stress-modifying carotid cuffs, PECAM-1 was shown to promote macrophage recruitment into lesions developing in areas of low shear stress.
CONCLUSIONS:
PECAM-1 on bone marrow cells is proatherogenic irrespective of the hemodynamic environment, however endothelial cell PECAM-1 is antiatherogenic in high shear environments. Thus, targeting this pathway therapeutically would require a cell-type and context-specific strategy.
AuthorsMatthew Harrison, Emily Smith, Ewan Ross, Robert Krams, Dolf Segers, Christopher D Buckley, Gerard B Nash, G Ed Rainger
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 4 Pg. 694-701 (Apr 2013) ISSN: 1524-4636 [Electronic] United States
PMID23372062 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Apolipoproteins E
  • Platelet Endothelial Cell Adhesion Molecule-1
Topics
  • Animals
  • Aorta (metabolism, pathology, physiopathology)
  • Aortic Diseases (genetics, metabolism, pathology, physiopathology, prevention & control)
  • Apolipoproteins E (deficiency, genetics)
  • Bone Marrow Cells (metabolism)
  • Bone Marrow Transplantation
  • Carotid Arteries (metabolism, pathology, physiopathology)
  • Carotid Artery Diseases (genetics, metabolism, pathology, physiopathology)
  • Diet, High-Fat
  • Disease Models, Animal
  • Endothelial Cells (metabolism, pathology)
  • Female
  • Genotype
  • Hemodynamics
  • Macrophages (metabolism)
  • Male
  • Mechanotransduction, Cellular
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Plaque, Atherosclerotic (genetics, metabolism, pathology, physiopathology, prevention & control)
  • Platelet Endothelial Cell Adhesion Molecule-1 (genetics, metabolism)
  • Regional Blood Flow
  • Stress, Mechanical
  • Transplantation Chimera

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