We have generated homozygous trans¬genic mice (hpa‐tg) overexpressing human hepara¬nase (endo‐β‐D‐glucuronidase) in all tissues and char¬acterized the involvement of the enzyme in tissue morphogenesis, vascularization, and energy metabo¬lism. Biochemical analysis of heparan sulfate (HS) isolated from newborn mice and adult tissues re¬vealed 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 exhib¬ited 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 func¬tion, reflected also by electron microscopy examina¬tion of the kidney tissue. The hpa‐tg mice exhibited a reduced food consumption and body weight com¬pared with control mice. The effect of heparanase on tissue remodeling and morphogenesis was best dem¬onstrated 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 implan¬tation, food consumption, tissue remodeling, and vascularization.—Zcharia, E., Metzger, S., ChajekShaul, T., Aingorn, H., Elkin, M., Friedmann, Y., Weinstein, T., Li, J.‐P., Lindahl, U., Vlodavsky, I. Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior. FASEB J. 18, 252–263 (2004)