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.

Low and high affinity receptors mediate cellular uptake of heparanase

“…Applying a highly purified recombinant heparanase on the Qproteome GlycoArray, revealed high levels of N-linked mannose, in agreement with its high affinity to Concanavalin A lectin Zcharia et al, 2005), and low levels of bi-antennary structures and sialic acid (Table 1). Glycoanalysis obtained by the lectin array was confirmed by biochemical analysis (Table 1).…”

“…More recently, Verys et al have identified two additional cell surface receptors that mediate heparanase uptake, namely the low density lipoprotein receptor-related protein (LRP) and the mannose 6-phosphate receptor (MPR) as key elements in this process (Vreys et al, 2005), although a model that combine the three receptors has not been proposed. Heparanase has long been characterized as a glycoprotein and including Concanavalin A affinity chromatography in the purification scheme brought this feature into practice (Toyoshima and Nakajima, 1999;Zcharia et al, 2005). Six glycosylation sites were identified in the 50 kDa heparanase subunit (Hulett et al, 1999), and their role in protein secretion was established (Simizu et al, 2004), yet glycan biochemical analysis was not performed to date.…”

Modulation of the Heparanase-inhibiting Activity of Heparin through Selective Desulfation, Graded N-Acetylation, and Glycol Splitting

“…The remarkable heparanase-inhibitory activity of N-acetylated, glycol-split heparins together with the low levels of FGF-2 that they release from ECM and their inability to stimulate the mitogenic activity of FGF-2 indicates this class of chemically modified heparins as potential antiangiogenic and antimetastatic agents. These compounds also markedly inhibit wound angiogenesis in transgenic mice overexpressing the heparanase gene (65). Furthermore our preliminary experiments show that some of these heparin derivatives effectively abolish experimental lung colonization of intravenously administered B16-BL6 mouse melanoma cells (Ref.…”

Syndecan-1 and Its Expanding List of Contacts

“…Heparanase is overexpressed in myeloma cells 14 and in tissues after wounding. 15 Sdc1 with HS stubs rather than longer HSPGs is more susceptible to proteases that mediate shedding.…”

“…Bacterial infections and sterile injuries induce the upregulation of sdc1, 4 heparanase, 15 and of proteases capable of cleaving sdc1 and releasing an ectodomain fragment. 48 The sdc1 ectodomain added to cells in culture suppressed the growth of tumor cells but had no impact on contact-inhibited cell lines.…”