title: Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior.
abstract: We have generated homozygous transgenic mice (hpa-tg) overexpressing human heparanase (endo-beta-D-glucuronidase) in all tissues and characterized the involvement of the enzyme in tissue morphogenesis, vascularization, and energy metabolism. Biochemical analysis of heparan sulfate (HS) isolated from newborn mice and adult tissues revealed a profound decrease in the size of HS chains derived from hpa-tg vs. control mice. Despite this, the mice appeared normal, were fertile, and exhibited a normal life span. A significant increase in the number of implanted embryos was noted in the hpa-tg vs. control mice. Overexpression of heparanase resulted in increased levels of urinary protein and creatinine, suggesting an effect on kidney function, reflected also by electron microscopy examination of the kidney tissue. The hpa-tg mice exhibited a reduced food consumption and body weight compared with control mice. The effect of heparanase on tissue remodeling and morphogenesis was best demonstrated by the phenotype of the hpa-tg mammary glands, showing excess branching and widening of ducts associated with enhanced neovascularization and disruption of the epithelial basement membrane. The hpa-tg mice exhibited an accelerated rate of hair growth, correlated with high expression of heparanase in hair follicle keratinocytes and increased vascularization. Altogether, characterization of the hpa-tg mice emphasizes the involvement of heparanase and HS in processes such as embryonic implantation, food consumption, tissue remodeling, and vascularization.
authors.affiliation: Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Shula
authors.initials: S
authors.lastname: Metzger
authors.forename: Tova
authors.initials: T
authors.lastname: Chajek-Shaul
authors.forename: Helena
authors.initials: H
authors.lastname: Aingorn
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
authors.forename: Yael
authors.initials: Y
authors.lastname: Friedmann
authors.forename: Talia
authors.initials: T
authors.lastname: Weinstein
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.forename: Ulf
authors.initials: U
authors.lastname: Lindahl
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000818:Animals; D001835:Body Weight; D002417:Cattle; D003315:Cornea; D004847:Epithelial Cells; D005247:Feeding Behavior; D005260:Female; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006197:Hair / Q000254:growth & development; D018859:Hair Follicle / Q000098:blood supply / Q000166:cytology / Q000201:enzymology; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D008321:Mammary Glands, Animal / Q000098:blood supply / Q000201:enzymology / Q000254:growth & development; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D010641:Phenotype; D019076:Transgenes / Q000235:genetics; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006497:Heparan Sulfate; D000099175:Heparanase