Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice

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...

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Bibliographic Details
Published in:Journal of Clinical Investigation 2008, Vol.118 (11), p.3725
Main 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
Format: Report
Language:English
Subjects:
Care and treatment
Gene expression
Genetic aspects
Glycoproteins
Health aspects
Liver diseases
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Summary: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