期刊
BLOOD
卷 124, 期 24, 页码 3656-3665出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-04-572107
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资金
- National Institutes of Health (National Institute of General Medical Sciences) [GM103441]
- National Heart, Lung, and Blood Institute [HL085607, HL093242, HL118676]
- Department of Defense [W81XWH-11-1-0226]
- Oklahoma Center for the Advancement of Science [HR13-160, HR13-020]
- National Natural Science Foundation of China [30928010, 31400692]
- Jiangsu Provincial Special Program of Medical Science [BL2012005]
- Jiangsu Province's Key Medical Center [ZX201102]
- American Heart Association [SDG7410022]
O-glycosylation of podoplanin (PDPN) on lymphatic endothelial cells is critical for the separation of blood and lymphatic systems by interacting with platelet C-type lectin-like receptor 2 during development. However, how O-glycosylation controls endothelial PDPN function and expression remains unclear. In this study, we report that core 1 O-glycan-deficient or desialylated PDPN was highly susceptible to proteolytic degradation by various proteases, including metalloproteinases (MMP)-2/9. We found that the lymph contained activated MMP-2/9 and incubation of the lymph reduced surface levels of PDPN on core 1 O-glycan-deficient endothelial cells, but not on wild-type ECs. The lymph from mice with sepsis induced by cecal ligation and puncture, which contained bacteria-derived sialidase, reduced PDPN levels on wild-type ECs. The MMP inhibitor, GM6001, rescued these reductions. Additionally, GM6001 treatment rescued the reduction of PDPN level on lymphatic endothelial cells in mice lacking endothelial core 1 O-glycan or cecal ligation and puncture-treated mice. Furthermore, core 1 O-glycan-deficient or desialylated PDPN impaired platelet interaction under physiological flow. These data indicate that sialylated O-glycans of PDPN are essential for platelet adhesion and prevent PDPN from proteolytic degradation primarily mediated by MMPs in the lymph.
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