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Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice

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Abstract

Wounds notoriously accumulate lactate as a consequence of both anaerobic and aerobic glycolysis following microcirculation disruption, immune activation, and increased cell proliferation. Several pieces of evidence suggest that lactate actively participates in the healing process through the activation of several molecular pathways that collectively promote angiogenesis. Lactate indeed stimulates endothelial cell migration and tube formation in vitro, as well as the recruitment of circulating vascular progenitor cells and vascular morphogenesis in vivo. In this study, we examined whether the pro-angiogenic potential of lactate may be exploited therapeutically to accelerate wound healing. We show that lactate delivered from a Matrigel matrix improves reperfusion and opposes muscular atrophy in ischemic hindlimb wounds in mice. Both responses involve lactate-induced reparative angiogenesis. Using microdialysis and enzymatic measurements, we found that, contrary to poly-L-lactide (PLA), a subcutaneous implant of poly-D,L-lactide-co-glycolide (PLGA) allows sustained local and systemic lactate release. PLGA promoted angiogenesis and accelerated the closure of excisional skin wounds in different mouse strains. This polymer is FDA-approved for other applications, emphasizing the possibility of exploiting PLGA therapeutically to improve wound healing.

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Acknowledgments

This work was supported by grants from the European Research Council (FP7/2007-2013 ERC Independent Researcher Starting Grant No. 243188 TUMETABO to P.S.), an Action de Recherche Concertée from the Communauté Française de Belgique (to P.S. and O.F.), the Fondation Belge contre le Cancer (200-2008 to P.S. and O.F.), the Fonds National de la Recherche Scientifique Médicale (FRSM), the Association Française contre les Myopathies (AFM), and the Fonds National de la Recherche Scientifique (F.R.S.-FNRS). P.S. is a Research Associate and O.F. an honorary Research Director of the F.R.S.-FNRS. C.D.S. is a Télévie Research Fellow. The authors thank Elise Beneteau, Morgane Tardy and Claire Ploquin for excellent technical assistance, and Pharmacists at Pharmacie Digitale (Kraainem) for providing the cetomacrogol cream. Dedicated to the loving memory of Mrs Anne-Sophie Brouckaert, PharmD.

Ethics statement

All the procedures described in this study and pertaining to the use and care of small laboratory animals have been approved by UCL authorities according to Belgian National Animal Care Regulations.

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Authors and Affiliations

  1. Pole of Pharmacology, Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 53 box B1.53.09, 1200, Brussels, Belgium

    Paolo E. Porporato, Valéry L. Payen, Christophe J. De Saedeleer, Olivier Feron & Pierre Sonveaux

  2. Department of Pharmaceutics and Drug Delivery, Louvain Drug Research Institute, Université catholique de Louvain (UCL), Brussels, Belgium

    Véronique Préat

  3. Pole of Endocrinology, Diabetology and Nutrition, Université catholique de Louvain (UCL), Brussels, Belgium

    Jean-Paul Thissen

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  1. Paolo E. Porporato
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  2. Valéry L. Payen
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  3. Christophe J. De Saedeleer
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  4. Véronique Préat
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  6. Olivier Feron
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  7. Pierre Sonveaux
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Correspondence to Pierre Sonveaux.

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Porporato, P.E., Payen, V.L., De Saedeleer, C.J. et al. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 15, 581–592 (2012). https://doi.org/10.1007/s10456-012-9282-0

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  • DOI: https://doi.org/10.1007/s10456-012-9282-0

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