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

Item Type:	Article
Title:	Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice
Creators Name:	Fu, J. and Gerhardt, H. and McDaniel, J.M. and Xia, B. and Liu, X. and Ivanciu, L. and Ny, A. and Hermans, K. and Silasi-Mansat, R. and McGee, S. and Nye, E. and Ju, T. and Ramirez, M.I. and Carmeliet, P. and Cummings, R.D. and Lupu, F. and Xia, L.
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.
Keywords:	Cultured Cells, Endothelial Cells, Fatty Liver, Galactosyltransferases, Lymphatic Vessels, Microvessels, Transgenes, Transgenic Mice, Animals, Mice
Source:	Journal of Clinical Investigation
ISSN:	0021-9738
Publisher:	American Society for Clinical Investigation
Volume:	118
Number:	11
Page Range:	3725-3737
Date:	November 2008
Official Publication:	https://doi.org/10.1172/JCI36077
PubMed:	View item in PubMed

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