Lactate stimulates angiogenesis, prevents ischemic skeletal muscle atrophy and accelerates wound healing
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1
Université catholique de Louvain (UCL), Institute of Experimental and Clinical Research (IREC), Belgium
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2
Université catholique de Louvain (UCL), Louvain Drug Research Institute (LDRI), Belgium
Background and aim. Lactate is often merely considered as a by-product accumulating in tumors and wounds as a result of accelerated glycolysis. However, we previously showed that lactate in tumors increases angiogenesis, which can be inhibited by targeting lactate transport across the cell membrane with inhibitors of monocarboxylate transporter 1 (MCT1). A number of evidence from our work and from the work of others suggests that lactate actively participates in the healing process through the activation of several molecular pathways that collectively promote angiogenesis. Whether these activities of lactate can be exploited for therapeutic applications has never been demon-strated.
Methods. In this study, we evaluated lactate-induced reparative angiogenesis in mouse models of intravital microscopy, hindlimb ischemia and excisional skin wounds. Lactate was delivered as a sodium salt or from a biodegradable polymer. Intravital microdialysis and/or enzymatic assays on CMA600 were used to measure lactate in body fluids.
Results. We showed that, by inducing reparative angiogenesis and independently from its use as an energetic fuel, lactate improved reperfusion and opposed muscular atrophy in ischemic hind limb injuries. Conversely, the impairment of lactate flux by MCT1 inhibition strongly deregulated this process, further emphasizing the roles of lactate and MCT1 in physiopathology. We therefore decided to develop a wound-accelerating treatment based on lactate. Sodium lactate in the drinking water failed to increase plasma lactate levels in mice. We therefore developed another strategy and found using intravital microdialysis that subcutaneous implants of poly-D,L-lactide-co-glycolide (PLGA) allowed sustained local and systemic lactate release. We confirmed in excisional skin wounds that lactate when released from PLGA is a powerful inducer of angiogenesis and, therefore, can strongly improve healing processes in which angiogenesis is required.
Conclusions. Our study evidences that lactate promotes reparative angiogenesis, especially when delivered chronically from FDA-approved PLGA implants. PLGA may therefore be therapeutically exploitable to improve wound healing. Conversely, MCT1-selective inhibitors are currently developed for anticancer use. Our results suggest that they could impair physiological angiogenesis.
Acknowledgements
This work was supported by ERC Starting Grant 243188 TUMETABO to Pierre Sonveaux.
Keywords:
mct1,
Angiogenesis,
Lactate,
Wound Healing,
PLGA
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
2. Membrane transporter in intracellular and extracellular pH-control
Citation:
Payen
VL,
Porporato
PE,
De Saedeleer
CJ,
Préat
V,
Feron
O and
Sonveaux
P
(2014). Lactate stimulates angiogenesis, prevents ischemic skeletal muscle atrophy and accelerates wound healing.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00033
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Received:
16 Dec 2013;
Published Online:
07 Feb 2014.
*
Correspondence:
Prof. Pierre Sonveaux, Université catholique de Louvain (UCL), Institute of Experimental and Clinical Research (IREC), Brussels, 1200, Belgium, pierre.sonveaux@uclouvain.be