Pro-angiogenic effect of RANTES-loaded polysaccharide-based microparticles for a mouse ischemia therapy

• Published in: Scientific reports 2017-10, Vol.7 (1), p.13294-16, Article 13294
• Main Authors: Suffee, N., Le Visage, C., Hlawaty, H., Aid-Launais, R., Vanneaux, V., Larghero, J., Haddad, O., Oudar, O., Charnaux, N., Sutton, A.
• Format: Article
• Language: English
• Subjects: 631/532; 631/61/2298; Angiogenesis; Angiogenesis Inducing Agents - administration & dosage; Animals; Arteries; Binding sites; Biodegradability; Biodegradation; Biological effects; Biomarkers; CCR5 protein; CD44 antigen; Cell activation; Cell Movement - genetics; Cell surface; Chemokine CCL5 - administration & dosage; Chemokines; Disease Models, Animal; Drug Carriers - administration & dosage; Drug Delivery Systems; Extremities - blood supply; Extremities - pathology; Fluorescent Antibody Technique; Geriatry and gerontology; Glycosaminoglycans; Glycosaminoglycans - metabolism; Human health and pathology; Humanities and Social Sciences; Injections, Intramuscular; Ischemia; Ischemia - drug therapy; Leukocyte migration; Life Sciences; Lymphocytes T; Mice; Microparticles; multidisciplinary; Muscles - metabolism; Muscles - pathology; Neovascularization, Physiologic - drug effects; Oligomerization; Polysaccharides; Polysaccharides - chemistry; Progenitor cells; RANTES; Regeneration - drug effects; Rhumatology and musculoskeletal system; Saccharides; Science; Science (multidisciplinary); Stem cells; Syndecan
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-13444-7

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 [ 44 AANA 47 ]-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.