Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice
Jianxin Fu, … , Florea Lupu, Lijun Xia
Jianxin Fu, … , Florea Lupu, Lijun Xia
Published October 16, 2008
Citation Information: J Clin Invest. 2008;118(11):3725-3737. https://doi.org/10.1172/JCI36077.
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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 2

EHC T-syn–/– mice exhibit high embryonic and neonatal mortality, disorganized vasculature, and impaired lymphatic function.

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EHC T-syn–/– mice exhibit high embryonic and neonatal mortality, disorga...
(A) Representative E15.5 embryos showing dilated superficial vessels with scattered hemorrhages in an EHC T-syn–/– mouse compared with its T-syn+/+ littermate. Arrows indicate abnormal vessels and subcutaneous bleeding. (B) Postnatal survival curves for T-syn+/+ mice and EHC T-syn–/– mice. (C) Gross images of intestines of E17.5 T-syn+/+ and EHC T-syn–/– embryos. Arrows indicate vessels. (D) Gross images of P7 T-syn+/+ and EHC T-syn–/– jejuna. Arrows indicate lymphatic vessels. Asterisks indicate chylous ascites. (E) Four-week-old T-syn+/+ and EHC T-syn–/– ilea. Arrow indicates blood vessels. Widespread bleeding (overall pink color) is evident in the EHC T-syn–/– ileum. (F) Luminal surfaces of T-syn+/+ and EHC T-syn–/– ilea. Arrows indicate dilated, blood-filled lacteals of EHC T-syn–/– intestinal villi. (G) Histological sections of dorsal skin of E15.5 T-syn+/+ and EHC T-syn–/– embryos. The asterisk marks enlarged subcutaneous fascia indicating edema. (H) Histological imaging of small intestine villi from 4-week-old T-syn+/+ and EHC T-syn–/–mice. Arrows indicate potential blood-filled lymphatic vessels. Scale bars: 1 mm (A, C, D, and E); 50 μm (F–H).