期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 98, 期 7, 页码 4072-4077出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.061307098
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资金
- NHLBI NIH HHS [R37 HL041002, R37 HL41002] Funding Source: Medline
Stimulation of endothelial cells by various inflammatory mediators leads to release of Weibel-Palade bodies and therefore to exocytosis of both P-selectin (adhesion receptor for leukocytes) and von Willebrand factor (vWf) (platelet ligand), The potential role of vWf in leukocyte recruitment was investigated with the use of vWf-deficient mice. We report a strong reduction of leukocyte rolling in venules of vWf-deficient mice. Similarly, vWf deficiency led to a decrease in neutrophil recruitment in a cytokine-induced meningitis model as well as in early skin wounds. In all instances with an antibody that preferentially recognizes plasma membrane P-selectin, we observed a dramatic reduction in P-selectin expression at the cell surface of vWf-deficient endothelium, With confocal microscopy, we found that the typical rodlike shape of the Weihel-Palade body is missing in vWf -/- endothelial cells and that part of the P-selectin content in the vWf -/- cells colocalized with LAMP-1, a lysosomal marker. However, intracellular P-selectin levels were similar in tumor necrosis factor alpha- and lipopolysaccharide-activated cells of both genotypes, We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel-Palade body formation. This defect results in decreased P-selectin translocation to the cell surface and reduced leukocyte recruitment in early phases of inflammation.
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