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- Title
Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice.
- Authors
Jianxin Fu; Gerhardt, Holger; McDaniel, J. Michael; Baoyun Xia; Xiaowei Liu; Ivanciu, Lacramioara; Ny, Annelii; Hermans, Karlien; Silasi-Mansat, Robert; McGee, Samuel; Nye, Emma; Tongzhong Ju; Ramirez, Maria I.; Carmeliet, Peter; Cummings, Richard D.; Lupu, Florea; Lijun Xia; Fu, Jianxin; Xia, Baoyun; Liu, Xiaowei
- 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.
- Subjects
LIVER diseases; BILIARY tract; FATTY degeneration; IMMUNE system; FATTY liver; ORGANIC synthesis; ANIMAL experimentation; BLOOD vessels; CELL culture; COMPARATIVE studies; EPITHELIAL cells; GENES; LYMPHATICS; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; TRANSFERASES; EVALUATION research
- Publication
Journal of Clinical Investigation, 2008, Vol 118, Issue 11, p3725
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI36077