title: Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms.
abstract: Hypoxia serves as a physiologic cue to drive an angiogenic response via HIF-dependent mechanisms. Interestingly, minor elevation of lactate levels in the tissue produces the same effect under aerobic conditions. Aerobic glycolysis contributes to lactate accumulation in the presence of oxygen, especially under inflammatory conditions. We previously postulated that aerobic lactate accumulation, already known to stimulate collagen deposition, will also stimulate angiogenesis. If substantiated, this concept would advance understanding of wound healing and aerobic angiogenesis because lactate accumulation has many aerobic sources. In this study, Matrigel plugs containing a powdered, hydrolyzable lactate polymer were implanted into the subcutaneous space of mice. Lactate monomer concentrations in the implant were consistent with wound levels for more than 11 days. They induced little inflammation but considerable VEGF production and were highly angiogenic, as opposed to controls. Arterial hypoxia abrogated angiogenesis. Furthermore, inhibition of lactate dehydrogenase by using oxamate also prevented the angiogenic effects of lactate. Lactate monomer, at concentrations found in cutaneous wounds, stabilized HIF-1alpha and increased VEGF levels in aerobically cultured human endothelial cells. Accumulated lactate, therefore, appears to convey the impression of "metabolic need" for vascularization, even in well-oxygenated and pH-neutral conditions. Lactate and oxygen together stimulate angiogenesis and matrix deposition.
authors.affiliation: Wound Healing Laboratory, University of California-San Francisco, San Francisco, California 94143-0522, USA. HuntT@surgery.ucsf.edu
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hunt
authors.forename: Rummana S
authors.initials: RS
authors.lastname: Aslam
authors.forename: Stefan
authors.initials: S
authors.lastname: Beckert
authors.forename: Silvia
authors.initials: S
authors.lastname: Wagner
authors.forename: Q Perveen
authors.initials: QP
authors.lastname: Ghani
authors.forename: M Zamirul
authors.initials: MZ
authors.lastname: Hussain
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
mesh_terms: D000818:Animals; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D005260:Female; D006868:Hydrolysis; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry; D051379:Mice; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004338:Drug Combinations; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D007770:L-Lactate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D010100:Oxygen