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OBJECTIVE: 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.

Original publication

DOI

10.1161/ATVBAHA.112.300379

Type

Journal article

Journal

Arterioscler Thromb Vasc Biol

Publication Date

04/2013

Volume

33

Pages

694 - 701

Keywords

Animals, Aorta, Aortic Diseases, Apolipoproteins E, Bone Marrow Cells, Bone Marrow Transplantation, Carotid Arteries, Carotid Artery Diseases, Diet, High-Fat, Disease Models, Animal, Endothelial Cells, Female, Genotype, Hemodynamics, Macrophages, Male, Mechanotransduction, Cellular, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Plaque, Atherosclerotic, Platelet Endothelial Cell Adhesion Molecule-1, Regional Blood Flow, Stress, Mechanical, Transplantation Chimera