title: Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models.
abstract: Orchestration of the rapid formation and reorganization of new tissue observed in wound healing involves not only cells and polypeptides but also the extracellular matrix (ECM) microenvironment. The ability of heparan sulfate (HS) to interact with major components of the ECM suggests a key role for HS in maintaining the structural integrity of the ECM. Heparanase, an endoglycosidase-degrading HS in the ECM and cell surface, is involved in the enzymatic machinery that enables cellular invasion and release of HS-bound polypeptides residing in the ECM. Bioavailabilty and activation of multitude mediators capable of promoting cell migration, proliferation, and neovascularization are of particular importance in the complex setting of wound healing. We provide evidence that heparanase is normally expressed in skin and in the wound granulation tissue. Heparanase stimulated keratinocyte cell migration and wound closure in vitro. Topical application of recombinant heparanase significantly accelerated wound healing in a flap/punch model and markedly improved flap survival. These heparanase effects were associated with enhanced wound epithelialization and blood vessel maturation. Similarly, a marked elevation in wound angiogenesis, evaluated by MRI analysis and histological analyses, was observed in heparanase-overexpressing transgenic mice. This effect was blocked by a novel, newly developed, heparanase-inhibiting glycol-split fragment of heparin. These results clearly indicate that elevation of heparanase levels in healing wounds markedly accelerates tissue repair and skin survival that are mediated primarily by an enhanced angiogenic response.-Zcharia, E., Zilka, R., Yaar, A., Yacoby-Zeevi, O., Zetser, A., Metzger, S., Sarid, R., Naggi, A., Casu, B., Ilan, N., Vlodavsky, I., Abramovitch, R. Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models.
authors.affiliation: Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Rachel
authors.initials: R
authors.lastname: Zilka
authors.forename: Alon
authors.initials: A
authors.lastname: Yaar
authors.forename: Oron
authors.initials: O
authors.lastname: Yacoby-Zeevi
authors.forename: Anna
authors.initials: A
authors.lastname: Zetser
authors.forename: Shula
authors.initials: S
authors.lastname: Metzger
authors.forename: Ronit
authors.initials: R
authors.lastname: Sarid
authors.forename: Annamaria
authors.initials: A
authors.lastname: Naggi
authors.forename: Benito
authors.initials: B
authors.lastname: Casu
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Rinat
authors.initials: R
authors.lastname: Abramovitch
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D016466:CHO Cells / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D005122:Exudates and Transudates / Q000201:enzymology; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000201:enzymology; D014162:Transfection / Q000379:methods; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000201:enzymology / Q000378:metabolism; D000099175:Heparanase
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D005966:Glucuronidase; D000099175:Heparanase