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

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.

• Authors: Jianxin Fu, Holger Gerhardt, J Michael McDaniel, Baoyun Xia, Xiaowei Liu, Lacramioara Ivanciu, Annelii Ny, Karlien Hermans, Robert Silasi-Mansat, Samuel McGee, Emma Nye, Tongzhong Ju, Maria I Ramirez, Peter Carmeliet, Richard D Cummings, Florea Lupu, Lijun Xia
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 118 Issue 11 Pg. 3725-37 (Nov 2008) ISSN: 0021-9738 [Print] United States
• PMID: 18924607 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• C1galt1 protein, mouse
• Galactosyltransferases

Topics

• Animals
• Cells, Cultured
• Endothelial Cells (immunology, metabolism, ultrastructure)
• Fatty Liver (immunology, metabolism)
• Galactosyltransferases (deficiency, genetics)
• Lymphatic Vessels (immunology, metabolism, ultrastructure)
• Mice
• Mice, Transgenic
• Microvessels (immunology, metabolism, ultrastructure)
• Transgenes