Abstract
Peripheral arterial disease results from the chronic obstruction of arteries leading to critical hindlimb ischemia. The aim was to develop a new therapeutic strategy of revascularization by using biodegradable and biocompatible polysaccharides-based microparticles (MP) to treat the mouse hindlimb ischemia. For this purpose, we deliver the pro-angiogenic chemokine Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES)/CCL5 in the mouse ischemic hindlimb, in solution or incorporated into polysaccharide-based microparticles. We demonstrate that RANTES-loaded microparticles improve the clinical score, induce the revascularization and the muscle regeneration in injured mice limb. To decipher the mechanisms underlying RANTES effects in vivo, we demonstrate that RANTES increases the spreading, the migration of human endothelial progenitor cells (EPC) and the formation of vascular network. The main receptors of RANTES i.e. CCR5, syndecan-4 and CD44 expressed at endothelial progenitor cell surface are involved in RANTES-induced in vitro biological effects on EPC. By using two RANTES mutants, [E66A]-RANTES with impaired ability to oligomerize, and [44AANA47]-RANTES mutated in the main RANTES-glycosaminoglycan binding site, we demonstrate that both chemokine oligomerization and binding site to glycosaminoglycans are essential for RANTES-induced angiogenesis in vitro. Herein we improved the muscle regeneration and revascularization after RANTES-loaded MP local injection in mice hindlimb ischemia.
Highlights
The chronic obstruction of arteries is associated with a vessel wall resistance and a reduction of blood flow leading to critical limb ischemia
On various cell types, that RANTES binds to its specific G protein-coupled receptors (GPCR) CCR1, CCR3 and CCR5 and to proteoglycans such as syndecan (SDC)-1, SDC-4 and CD449–12
Cross-linked hydrogels based on biodegradable polysaccharides pullulan and dextran developed by our laboratory can be loaded with peptides and have been shown to favor the delivery of proangiogenic factors[25]
Summary
The chronic obstruction of arteries is associated with a vessel wall resistance and a reduction of blood flow leading to critical limb ischemia. Protein-based therapies using proangiogenic growth factors have been demonstrated to induce neovascularization in animal models of peripheral arterial diseases[1]. Basic Fibroblast Growth Factor (bFGF) constitutes the only protein-based therapy administered in clinical trials enrolling patients suffering from atherosclerotic peripheral arterial diseases[1]. The third clinical trial, published in 2002, implicated intra-arterial bFGF injection and resulted in a 90-day change in peak walking time, ankle-brachial pressure index and demonstrated safety[4]. Another therapeutic axis for ischemia is represented by cell therapy. We demonstrated that local administration of this chemokine following the ischemic injury could promote the early reparative events preceding the neovessel formation, muscle regeneration and the restoration of blood flow
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