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Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models

Eyal Zcharia^*,1, Rachel Zilka^,,1, Alon Yaar, Oron Yacoby-Zeevi, Anna Zetser, Shula Metzger^||,, Ronit Sarid, Annamaria Naggi^||,, Benito Casu^||,, Neta Ilan^,,2, Israel Vlodavsky^,2 and Rinat Abramovitch

^* Departments of Oncology,
^|| Medicine and
Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
InSight Biopharmaceuticals, Rabin Science Park, Rehovot, Israel;
Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel;
Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; and
^|| G. Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy

²Correspondence: Cancer and Vascular Biology Research Center, Faculty of Medicine, Technion, P.O. Box 9649, Haifa 31096, Israel. E-mail: vlodavsk{at}cc.huji.ac.il; netailan{at}tx.technion.ac.il

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.

Key Words: heparan sulfate • keratinocytes • blood vessel maturation • extracellular matrix • MRI • tissue repair • wound fluid

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