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Title: Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice
Authors: Fu, Jianxin
Gerhardt, Holger
McDaniel, J. Michael
Xia, Baoyun
Liu, Xiaowei
Ivanciu, Lacramioara
Ny, Annelii
Hermans, Karlien
Silasi-Mansat, Robert
McGee, Samuel
Nye, Emma
Ju, Tongzhong
Ramirez, Maria I
Carmeliet, Peter
Cummings, Richard D
Lupu, Florea
Xia, Lijun # ×
Issue Date: Nov-2008
Publisher: Amer soc clinical investigation inc
Series Title: Journal of Clinical Investigation vol:118 issue:11 pages:3725-3737
Abstract: Mucin-type O-glycans (O-glycans) are highly expressed in vascular ECs. However, it is not known whether they are important for vascular development. To investigate the roles of EC O-glycans, we generated mice lacking T-synthase, a glycosyltransferase encoded by the gene C1galt1 that is critical for the biosynthesis of core 1-derived O-glycans, in ECs and hematopoietic cells (termed here EHC T-syn(-/-) mice). EHC T-syn(-/-) mice exhibited embryonic and neonatal lethality associated with disorganized and blood-filled lymphatic vessels. Bone marrow transplantation and EC C1galt1 transgene rescue demonstrated that lymphangiogenesis specifically requires EC O-glycans, and intestinal lymphatic microvessels in EHC T-syn(-/-) mice expressed a mosaic of blood and lymphatic EC markers. The level of O-glycoprotein podoplanin was significantly reduced in EHC T-syn(-/-) lymphatics, and podoplanin-deficient mice developed blood-filled lymphatics resembling EHC T-syn(-/-) defects. In addition, postnatal inactivation of C1galt1 caused blood/lymphatic vessel misconnections that were similar to the vascular defects in the EHC T-syn(-/-) mice. One consequence of eliminating T-synthase in ECs and hematopoietic cells was that the EHC T-syn(-/-) pups developed fatty liver disease, because of direct chylomicron deposition via misconnected portal vein and intestinal lymphatic systems. Our studies therefore demonstrate that EC O-glycans control the separation of blood and lymphatic vessels during embryonic and postnatal development, in part by regulating podoplanin expression.
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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