Systemic inactivation of <i>Hs6st1</i> in mice is associated with late postnatal mortality without major defects in organogenesis

Izvolsky, Konstantin I.; Lü, Jining; Martin, Greg S.; Albrecht, Kenneth H.; Cardoso, Wellington V.

doi:10.1002/dvg.20355

Cited by 32 publications

(19 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gengrinovitch et al (53) have suggested glypican-1 as a VEGF 165 -binding proteoglycan, but endothelial cells express other membrane proteoglycans as well (54). Studies are underway to identify the functional HSPG that interacts with VEGFR2 and VEGF 165 and whether the interaction with heparan sulfate depends on the arrangement of sulfate residues in the chain, e.g., by examining how hyperpermeability is affected in tissue-specific mutants altered in uronyl 2-O-sulfation (55) and glucosaminyl 6-O-sulfation (56). Systemic mutants altered in the expression of specific core proteins are also available, which should aid in the identification of the active proteoglycan(s) in this system (57).…”

Section: Discussionmentioning

confidence: 99%

Heparan Sulfate Regulates VEGF165- and VEGF121-mediated Vascular Hyperpermeability

Fuster

Lawrence

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

VEGF was first described as vascular permeability factor, a potent inducer of vascular leakage. Genetic evidence indicates that VEGF-stimulated endothelial proliferation in vitro and angiogenesis in vivo depend on heparan sulfate, but a requirement for heparan sulfate in vascular hyperpermeability has not been explored. Here we show that altering endothelial cell heparan sulfate biosynthesis in vivo decreases hyperpermeability induced by both VEGF 165 and VEGF 121 . Because VEGF 121 does not bind heparan sulfate, the requirement for heparan sulfate suggested that it interacted with VEGF receptors rather than the ligand. By applying proximity ligation assays to primary brain endothelial cells, we show a direct interaction in situ between heparan sulfate and the VEGF receptor, VEGFR2. Furthermore, the number of heparan sulfate-VEGFR2 complexes increased in response to both VEGF 165 and VEGF 121 . Genetic or heparin lyase-mediated alteration of endothelial heparan sulfate attenuated phosphorylation of VEGFR2 in response to VEGF 165 and VEGF 121 , suggesting that the functional VEGF receptor complex contains heparan sulfate. Pharmacological blockade of heparan sulfate-protein interactions inhibited hyperpermeability in vivo, suggesting heparan sulfate as a potential target for treating hyperpermeability associated with ischemic disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Heparan Sulfate Regulates VEGF165- and VEGF121-mediated Vascular Hyperpermeability

Fuster

Lawrence

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…flox and Hs2st flox mice have been previously described (20,27). Hs6st2 KO mice were obtained from Lexicon Genetics via Mutant Mouse Regional Resource Centers (MMRRC:011715-UCD).…”

Section: Mice-hs6st1mentioning

confidence: 99%

Lacrimal Gland Development and Fgf10-Fgfr2b Signaling Are Controlled by 2-O- and 6-O-sulfated Heparan Sulfate

Carbe

Tao

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Heparan sulfate, an extensively sulfated glycosaminoglycan abundant on cell surface proteoglycans, regulates intercellular signaling through its binding to various growth factors and receptors. In the lacrimal gland, branching morphogenesis depends on the interaction of heparan sulfate with Fgf10-Fgfr2b. To address if lacrimal gland development and FGF signaling depends on 2-O-sulfation of uronic acids and 6-O-sulfation of glucosamine residues, we genetically ablated heparan sulfate 2-O and 6-O sulfotransferases (Hs2st, Hs6st1, and Hs6st2) in developing lacrimal gland. Using a panel of phage display antibodies, we confirmed that these mutations disrupted 2-O and/or 6-O but not N-sulfation of heparan sulfate. The Hs6st mutants exhibited significant lacrimal gland hypoplasia and a strong genetic interaction with Fgf10, demonstrating the importance of heparan sulfate 6-O sulfation in lacrimal gland FGF signaling. Altering Hs2st caused a much less severe phenotype, but the Hs2st;Hs6st double mutants completely abolished lacrimal gland development, suggesting that both 2-O and 6-O sulfation of heparan sulfate contribute to FGF signaling. Combined Hs2st;Hs6st deficiency synergistically disrupted the formation of Fgf10-Fgfr2b-heparan sulfate complex on the cell surface and prevented lacrimal gland induction by Fgf10 in explant cultures. Importantly, the Hs2st;Hs6st double mutants abrogated FGF downstream ERK signaling. Therefore, Fgf10-Fgfr2b signaling during lacrimal gland development is sensitive to the content or arrangement of O-sulfate groups in heparan sulfate. To our knowledge, this is the first study to show that simultaneous deletion of Hs2st and Hs6st exhibits profound FGF signaling defects in mammalian development.Heparan sulfate is a cell-surface glycosaminoglycan playing important roles in the transport and signaling of multiple growth factors, including Hedgehog, Wnt, bone morphogenic protein (BMP), and fibroblast growth factor (FGF) (1-3). Heparan sulfate is first synthesized from the activated monosaccharides, UDP-glucuronic acid and UDP-N-acetylglucosamine, by an Ext copolymerase complex to form a copolymer of glucuronic acid and N-acetylglucosamine. Polymerization is followed by N-deacetylation/N-sulfation of subsets of N-acetylglucosamine residues by N-deacetylase-N-sulfotransferase (Ndst) 2 enzymes (4). Because of the incomplete processing by the Ndst enzymes, the polysaccharide backbone is divided into stretches of variable length of N-sulfated disaccharides (NS domains) and N-acetylated disaccharides (NA domains). A portion of the D-glucuronic acid residues in the NS domains is next converted by glucuronyl C5-epimerase (Hsepi) into l-iduronic acids. A 2-O-sulfotransferase (Hs2st) transfers a sulfate group to the C-2 carbon of the iduronic acids and less frequently to glucuronic acid. Finally, 6-O-sulfotransferases (Hs6st) and more rarely 3-O-sulfotransferases (Hs3st) add sulfate groups to the C-6 and C-3 carbon of the glucosamine residues, respectively. These reactions do not go to completion, lea...

show abstract

“…The biological and physiological importance of Hs6st-1 was determined by examining Hs6st-1 null (Hs6st-1−/−) mice. 35,36 Most of the Hs6st-1 −/− mice die between embryonic day 15.5 (E15.5) and the perinatal stage, and a low percentage of the mutant mice that survive are considerably smaller than their wild-type littermates (Table I). Some of the Hs6st-1 −/− mice exhibited developmental abnormalities, including a ~ 50 % reduction in the number of fetal microvessels in the labyrinthine zone of the developing placenta.…”

Section: Endothelial Heparan Sulfate In Developmental and Physiolomentioning

confidence: 99%

Endothelial Heparan Sulfate in Angiogenesis

Fuster

Wang

2010

Progress in Molecular Biology and Translational Science

View full text Add to dashboard Cite

Heparan sulfate (HS) is a linear polysaccharide composed of 50–200 glucosamine and uronic acid (glucuronic acid or iduronic acid) disaccharide repeats with epimerization and various sulfation modifications. HS is covalently attached to core proteins to form HS-proteoglycans. Most of the functions of HS-proteoglycans are mediated by their HS moieties. The biosynthesis of HS is initiated by chain polymerization and is followed by stepwise modification reactions, including sulfation and epimerization. These modifications generate ligand-binding sites that modulate cell functions and activities of proteinases and/or proteinase inhibitors. HS is abundantly expressed in developing and mature vasculature, and understanding its roles in vascular biology and related human diseases is an area of intense investigation. In this chapter, we summarize the significant recent advances in our understanding of the roles of HS in developmental and pathological angiogenesis with a major focus on studies using transgenic as well as gene knockout/knockdown models in mice and zebrafish. These studies have revealed that HS critically regulates angiogenesis by playing a proangiogenic role, and this regulatory function critically depends on HS fine structure. The latter is responsible for facilitating cell-surface binding of various proangiogenic growth factors that in turn mediate endothelial growth signaling. In cancer, mouse studies have revealed important roles for endothelial cell-surface HS as well as matrix-associated HS, wherein signaling by multiple growth factors as well as matrix storage of growth factors may be regulated by HS. We also discuss important mediators that may fine-tune such regulation, such as heparanase and sulfatases; and models wherein targeting HS (or core protein) biosynthesis may affect tumor growth and vascularization. Finally, the importance of targeting HS in other human diseases wherein angiogenesis may play pathophysiologic (or even therapeutic) roles is considered.

show abstract

Systemic inactivation of Hs6st1 in mice is associated with late postnatal mortality without major defects in organogenesis

Cited by 32 publications

References 38 publications

Heparan Sulfate Regulates VEGF165- and VEGF121-mediated Vascular Hyperpermeability

Heparan Sulfate Regulates VEGF165- and VEGF121-mediated Vascular Hyperpermeability

Lacrimal Gland Development and Fgf10-Fgfr2b Signaling Are Controlled by 2-O- and 6-O-sulfated Heparan Sulfate

Endothelial Heparan Sulfate in Angiogenesis

Contact Info

Product

Resources

About