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

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

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Figure 8

EHC T-syn–/– mice develop fatty liver disease.

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EHC T-syn–/– mice develop fatty liver disease. (A) Representative im...
(A) Representative images of mesenteric vessels. (B) EHC T-syn–/– mice develop fatty livers. Arrows indicate white-colored areas of lipid deposition in the P7 EHC T-syn–/– liver. (C) Representative transmission electron microscopic images of T-syn+/+ and EHC T-syn–/– livers. Arrows indicate liver sinusoidal endothelium. Arrowheads mark lipid inclusions. (D) Abnormal lipid deposition in liver of EHC T-syn–/– mice revealed by Nile red staining (red). (E) Lipid analysis of serum and liver tissues. TC, total cholesterol; Trg, triglycerides. (F) The portal vein (PV) of a 7-week-old EHC T-syn–/– mouse, but not of a T-syn+/+ mouse, was visualized after mice were gavaged with the fluorescent lipid BODIPY FL C16. BD, bile duct. (G) Model illustrating how misconnections of intestinal blood and lymphatic vessels leads to abnormal lipid transport in EHC T-syn–/– mice. Data represent the mean ± SEM of 3 independent experiments (n = 3–5 mice per group). Scale bars: 2 mm (A and B); 2 μm (C); 50 μm (D); 1 mm (F).