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


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.
Centre for Cardiovascular Sciences, The Medical School, University of Birmingham, Birmingham, UK. m.j.harrison.1@bham.ac.uk
Matthew
M
Harrison
Emily
E
Smith
Ewan
E
Ross
Robert
R
Krams
Dolf
D
Segers
Christopher D
CD
Buckley
Gerard B
GB
Nash
G Ed
GE
Rainger
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D006439:Hemodynamics; D008264:Macrophages / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D018183:Transplantation Chimera
D001057:Apolipoproteins E; D019408:Platelet Endothelial Cell Adhesion Molecule-1