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*
Amgen Institute, Toronto, Ontario, Canada;
Department of Inflammation, Amgen Boulder, Boulder, CO 80301;
Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada;
§
Amgen, Thousand Oaks, CA 91320; and
¶
Department of Pathology, Cornell University Medical College, New York, NY 10021
Platelet/endothelial cell adhesion molecule-1 (PECAM-1; CD31), a member of the Ig superfamily, is expressed strongly at endothelial cell-cell junctions, on platelets, and on most leukocytes. CD31 has been postulated to play a role in vasculogenesis and angiogenesis, and has been implicated as a key mediator of the transendothelial migration of leukocytes. To further define the physiologic role of CD31, we used targeted gene disruption of the CD31 gene in embryonic stem cells to generate CD31-deficient mice. CD31-deficient mice (CD31KO) are viable and born at the expected Mendelian frequency, remain healthy, and exhibit no obvious vascular developmental defects. In response to inflammatory challenge, polymorphonuclear leukocytes of CD31KO mice are arrested between the vascular endothelium and the basement membrane of inflammatory site mesenteric microvessels, confirming a role for CD31 in the migration of neutrophils through the subendothelial extracellular matrix. Normal numbers of leukocytes are recovered from inflammatory sites in CD31KO mice, however, suggesting that the defect in leukocyte migration across basal lamina observed in the absence of CD31 may be compensated for by the use of other adhesion molecules, or possibly an increased rate of migration. Homing of T lymphocytes in vivo is normal, and CD31KO mice are able to mount a cutaneous hypersensitivity response normally. In addition, CD31-mediated homophilic adhesion does not appear to play a role in platelet aggregation in vitro. This study provides genetic evidence that CD31 is involved in transbasement membrane migration, but does not play an obligatory role in either vascular development or leukocyte migration.
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A. K. Nath, J. Enciso, M. Kuniyasu, X.-Y. Hao, J. A. Madri, and E. Pinter Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy Development, May 15, 2004; 131(10): 2485 - 2496. [Abstract] [Full Text] [PDF]
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 T. Furusawa, K. Ohkoshi, C. Honda, S. Takahashi, and T. Tokunaga Embryonic Stem Cells Expressing Both Platelet Endothelial Cell Adhesion Molecule-1 and Stage-Specific Embryonic Antigen-1 Differentiate Predominantly into Epiblast Cells in a Chimeric Embryo Biol Reprod, May 1, 2004; 70(5): 1452 - 1457. [Abstract] [Full Text] [PDF]
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R. E. Young, R. D. Thompson, K. Y. Larbi, M. La, C. E. Roberts, S. D. Shapiro, M. Perretti, and S. Nourshargh Neutrophil Elastase (NE)-Deficient Mice Demonstrate a Nonredundant Role for NE in Neutrophil Migration, Generation of Proinflammatory Mediators, and Phagocytosis in Response to Zymosan Particles In Vivo J. Immunol., April 1, 2004; 172(7): 4493 - 4502. [Abstract] [Full Text] [PDF]
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V. Rathore, M. A. Stapleton, C. A. Hillery, R. R. Montgomery, T. C. Nichols, E. P. Merricks, D. K. Newman, and P. J. Newman PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets Blood, November 15, 2003; 102(10): 3658 - 3664. [Abstract] [Full Text] [PDF]
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T. Ishida, R. K. Kundu, E. Yang, K.-i. Hirata, Y.-D. Ho, and T. Quertermous Targeted Disruption of Endothelial Cell-selective Adhesion Molecule Inhibits Angiogenic Processes in Vitro and in Vivo J. Biol. Chem., September 5, 2003; 278(36): 34598 - 34604. [Abstract] [Full Text] [PDF]
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D. GRATZINGER, S. CANOSA, B. ENGELHARDT, and J. A. MADRI Platelet endothelial cell adhesion molecule-1 modulates endothelial cell motility through the small G-protein Rho FASEB J, August 1, 2003; 17(11): 1458 - 1469. [Abstract] [Full Text] [PDF]
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G. W. Payne, J. A. Madri, W. C. Sessa, and S. S. Segal Abolition of arteriolar dilation but not constriction to histamine in cremaster muscle of eNOS-/- mice Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H493 - H498. [Abstract] [Full Text] [PDF]
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P. J. Newman and D. K. Newman Signal Transduction Pathways Mediated by PECAM-1: New Roles for an Old Molecule in Platelet and Vascular Cell Biology Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 953 - 964. [Abstract] [Full Text] [PDF]
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A. R. Burns, C. W. Smith, and D. C. Walker Unique Structural Features That Influence Neutrophil Emigration Into the Lung Physiol Rev, April 1, 2003; 83(2): 309 - 336. [Abstract] [Full Text] [PDF]
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C. D. O'Brien, P. Lim, J. Sun, and S. M. Albelda PECAM-1-dependent neutrophil transmigration is independent of monolayer PECAM-1 signaling or localization Blood, April 1, 2003; 101(7): 2816 - 2825. [Abstract] [Full Text] [PDF]
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A. Solowiej, P. Biswas, D. Graesser, and J. A. Madri Lack of Platelet Endothelial Cell Adhesion Molecule-1 Attenuates Foreign Body Inflammation because of Decreased Angiogenesis Am. J. Pathol., March 1, 2003; 162(3): 953 - 962. [Abstract] [Full Text] [PDF]
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J. Dangerfield, K. Y. Larbi, M.-T. Huang, A. Dewar, and S. Nourshargh PECAM-1 (CD31) Homophilic Interaction Up-Regulates {alpha}6{beta}1 on Transmigrated Neutrophils In Vivo and Plays a Functional Role in the Ability of {alpha}6 Integrins to Mediate Leukocyte Migration through the Perivascular Basement Membrane J. Exp. Med., November 4, 2002; 196(9): 1201 - 1212. [Abstract] [Full Text] [PDF]
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P. F. Lalor, S. Edwards, G. McNab, M. Salmi, S. Jalkanen, and D. H. Adams Vascular Adhesion Protein-1 Mediates Adhesion and Transmigration of Lymphocytes on Human Hepatic Endothelial Cells J. Immunol., July 15, 2002; 169(2): 983 - 992. [Abstract] [Full Text] [PDF]
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R. Wilkinson, A. B. Lyons, D. Roberts, M.-X. Wong, P. A. Bartley, and D. E. Jackson Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) acts as a regulator of B-cell development, B-cell antigen receptor (BCR)-mediated activation, and autoimmune disease Blood, June 17, 2002; 100(1): 184 - 193. [Abstract] [Full Text] [PDF]
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