Different cell cycle responses of wound healing protagonists to transient in vitro hypoxia

Oberringer, Martin; Jennewein, Martina; Motsch, Sandra E.; Pohlemann, Tim; Seekamp, Andreas

doi:10.1007/s00418-005-0782-5

Cited by 22 publications

(26 citation statements)

References 28 publications

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“…Hypoxia can initiate neovascularization by inducing growth factors (12,19,36,39). However, sustained periods of equally severe hypoxia limit neovascularization (17), proliferation of dermal cells (28), collagen deposition (33), bacterial killing and resistance to infection (3), and more severe hypoxia causes tissue death and dysfunction (33). On the other hand, supplemental O 2, in vivo accelerates wound vessel growth (12,16,17), collagen deposition (34,41) and angiogenesis (12).…”

Section: Introductionmentioning

confidence: 99%

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Hunt

Aslam

Beckert

et al. 2007

Antioxidants & Redox Signaling

227

177

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Hypoxia serves as a physiological cue to drive 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 have 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, hydrolysable lactate polymer were implanted into the subcutaneous space of mice. Lactate monomer concentrations in the implant were consistent with wound levels for over 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 using oxamate also prevented the angiogenic effects of lactate. Lactate monomer, at concentrations found in cutaneous wounds, stabilized HIF-1α 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 both stimulate angiogenesis and matrix deposition.

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Section: Introductionmentioning

confidence: 99%

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Hunt

Aslam

Beckert

et al. 2007

Antioxidants & Redox Signaling

227

177

View full text Add to dashboard Cite

show abstract

“…Although hypoxia is generally recognized as a physiological cue to induce angiogenesis (7-10), severe hypoxia cannot sustain the growth of functional blood vessels (2,(11)(12)(13)(14). Interestingly, like hypoxia, hyperoxia also induces the expression of angiogenic factors and supports wound angiogenesis and healing (2,(15)(16)(17).…”

mentioning

confidence: 99%

Wound angiogenesis as a function of tissue oxygen tension: A mathematical model

Schugart

Friedman

Zhao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

165

188

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“…Hypoxia is generally recognized as a physiological cue to induce angiogenesis (6)(7)(8)(9). However, severe hypoxia, as is often noted in infected open wounds, cannot sustain the growth of functional blood vessels (10)(11)(12)(13)(14). Although different groups have reported mathematical models for wounds, the ischemic wound which represents the most clinically challenging type of wounds remains to be modeled.…”

mentioning

confidence: 99%

A mathematical model of ischemic cutaneous wounds

Xue

Friedman²,

Sen³

2009

Proc. Natl. Acad. Sci. U.S.A.

114

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Chronic wounds represent a major public health problem affecting 6.5 million people in the United States. Ischemia, primarily caused by peripheral artery diseases, represents a major complicating factor in cutaneous wound healing. In this work, we sought to develop a mathematical model of ischemic dermal wounds. The model consists of a coupled system of partial differential equations in the partially healed region, with the wound boundary as a free boundary. The extracellular matrix (ECM) is assumed to be viscoelastic, and the free boundary moves with the velocity of the ECM at the boundary. The model equations involve the concentration of oxygen, PDGF and VEGF, the densities of macrophages, fibroblasts, capillary tips and sprouts, and the density and velocity of the ECM. Simulations of the model demonstrate how ischemic conditions may limit macrophage recruitment to the wound-site and impair wound closure. The results are in general agreement with experimental findings.wound healing | ischemia | free boundary | viscoelasticity T he public health impact of chronic wounds is staggering. An estimated 1.3-3 million U.S. individuals are believed to have pressure ulcers and as many as 10 -15% of the 20 million individuals with diabetes are at risk of developing chronic ulcers. Many more have venous ulcers or wounds that result from arterial disease. Treating these wounds costs an estimated $5-$10 billion each year (1). The ability to repair the injured skin tissue is an evolutionarily conserved physiological defense response aimed at reestablishing the barrier function of the skin. Wound healing represents the outcome of a large number of interrelated biological events that are orchestrated over a temporal sequence in response to injury and its microenvironment. The process involves interactions among different soluble chemical mediators, different types of cells and the extracellular matrix (ECM). Wound healing, under normal conditions, is typically represented by four overlapping stages: haemostasis, inflammation, proliferation, and remodeling (2, 3). During haemostasis, which occurs immediately after injury, clotting factors are delivered by platelets to the injured site to stop bleeding. At the wound site, platelets also release chemokines such as PDGF, which also recruits bloodborne cells to the wound. During the inflammatory phase, mast cells release granules that contain enzymes promoting vascular leakiness. This release enables neutrophils to migrate from the blood vessels into the wound site. Macrophages, differentiated from monocytes, also migrate into the wound and, together with neutrophils, degrade and remove necrotic tissue and kill infectious pathogens. Macrophages also enhance the production of growth factors secreted by platelets to attract fibroblasts and endothelial cells. The proliferative phase is characterized by the production of ECM by fibroblasts, and by the directed growth and movement of new blood vessels (angiogenesis) into the wound. The newly deposited ECM on the one hand serves as the b...

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Different cell cycle responses of wound healing protagonists to transient in vitro hypoxia

Cited by 22 publications

References 28 publications

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Wound angiogenesis as a function of tissue oxygen tension: A mathematical model

A mathematical model of ischemic cutaneous wounds

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