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Hyperglycemia-Induced Changes in Hyaluronan Contribute to Impaired Skin Wound Healing in Diabetes: Review and Perspective.

Shakya S, Wang Y, Mack JA, Maytin EV - Int J Cell Biol (2015)

Bottom Line: Ulcers and chronic wounds are a particularly common problem in diabetics and are associated with hyperglycemia.In this targeted review, we summarize evidence suggesting that defective wound healing in diabetics is causally linked, at least in part, to hyperglycemia-induced changes in the status of hyaluronan (HA) that resides in the pericellular coat (glycocalyx) of endothelial cells of small cutaneous blood vessels.Possible roles of newly recognized, cross-linked forms of HA, and interactions of a major HA receptor (CD44) with cytokine/growth factor receptors during hyperglycemia, are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Ulcers and chronic wounds are a particularly common problem in diabetics and are associated with hyperglycemia. In this targeted review, we summarize evidence suggesting that defective wound healing in diabetics is causally linked, at least in part, to hyperglycemia-induced changes in the status of hyaluronan (HA) that resides in the pericellular coat (glycocalyx) of endothelial cells of small cutaneous blood vessels. Potential mechanisms through which exposure to high glucose levels causes a loss of the glycocalyx on the endothelium and accelerates the recruitment of leukocytes, creating a proinflammatory environment, are discussed in detail. Hyperglycemia also affects other cells in the immediate perivascular area, including pericytes and smooth muscle cells, through exposure to increased cytokine levels and through glucose elevations in the interstitial fluid. Possible roles of newly recognized, cross-linked forms of HA, and interactions of a major HA receptor (CD44) with cytokine/growth factor receptors during hyperglycemia, are also discussed.

No MeSH data available.


Related in: MedlinePlus

Skin fibroblasts with a larger HA glycocalyx are more responsive to TGF-β and produce more collagen when cultured in a high glucose medium. Skin fibroblasts from either wild type (WT) or Has1/3  mice were cultured in normal glucose (1 g/L) or in high glucose (4.5 g/L) in the absence or presence of TGF-β1 (2 ng/mL) in DMEM media with 1% FBS for 48 hours. (a) Erythrocyte exclusion assay to visualize the pericellular coat on WT and Has1/3  fibroblasts [51]. Cells were labeled with calcein to delineate the cell bodies. The HA glycocalyx is indicated between the white and yellow lines. (b) Western blot of protein from WT or Has1/3  fibroblasts, probed with an antibody to type 1 collagen. GAPDH, loading control. (c) Quantification of protein band intensities from two independent western analysis experiments, performed under the conditions shown in panel (b) and normalized to GAPDH. White bars, WT fibroblasts. Gray bars, Has1/3  fibroblasts. Error bars, mean ± half-range.
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fig2: Skin fibroblasts with a larger HA glycocalyx are more responsive to TGF-β and produce more collagen when cultured in a high glucose medium. Skin fibroblasts from either wild type (WT) or Has1/3 mice were cultured in normal glucose (1 g/L) or in high glucose (4.5 g/L) in the absence or presence of TGF-β1 (2 ng/mL) in DMEM media with 1% FBS for 48 hours. (a) Erythrocyte exclusion assay to visualize the pericellular coat on WT and Has1/3 fibroblasts [51]. Cells were labeled with calcein to delineate the cell bodies. The HA glycocalyx is indicated between the white and yellow lines. (b) Western blot of protein from WT or Has1/3 fibroblasts, probed with an antibody to type 1 collagen. GAPDH, loading control. (c) Quantification of protein band intensities from two independent western analysis experiments, performed under the conditions shown in panel (b) and normalized to GAPDH. White bars, WT fibroblasts. Gray bars, Has1/3 fibroblasts. Error bars, mean ± half-range.

Mentions: HA biology can be surprisingly cell-specific. Thus, while hyperglycemia causes problems in dermal microvessels by reducing HA in the EC glycocalyx, hyperglycemia affects dermal mesenchymal cells by increasing their HA glycocalyces. Work from the Tammi group showed that, in vascular smooth muscle cells (SMCs), high glucose promotes HA synthesis and HAS gene expression but impairs vascular SMC function as reflected by a reduced ability to contract collagen gels; this offers a potential mechanism whereby hyperglycemia could disturb vascular remodeling and contribute to arteriosclerosis [71]. Vigetti et al. showed that HMW-HA can protect human aortic SMCs against apoptosis induced by 4-methylumbelliferone (an HA synthesis inhibitor), suggesting that higher amounts of HA associated with SMCs increase their survival and might favor accumulation of SMCs in the vessel wall [72]. A similar relationship in which higher HA production appears to be protective against apoptosis was demonstrated in our studies of dermal fibroblasts [51]. Using HAS1/HAS3 double-knockout mice [51], we showed that fibroblasts compensate for the loss of HAS1 and HAS3 by overexpressing HAS2, resulting in an increase in HAS2 activity and synthesis of an enlarged HA glycocalyx relative to normal fibroblasts (Figure 2(a)). When exposed to apoptosis-inducing stress such as serum starvation, the HAS1/3 cells were less likely to die [51].


Hyperglycemia-Induced Changes in Hyaluronan Contribute to Impaired Skin Wound Healing in Diabetes: Review and Perspective.

Shakya S, Wang Y, Mack JA, Maytin EV - Int J Cell Biol (2015)

Skin fibroblasts with a larger HA glycocalyx are more responsive to TGF-β and produce more collagen when cultured in a high glucose medium. Skin fibroblasts from either wild type (WT) or Has1/3  mice were cultured in normal glucose (1 g/L) or in high glucose (4.5 g/L) in the absence or presence of TGF-β1 (2 ng/mL) in DMEM media with 1% FBS for 48 hours. (a) Erythrocyte exclusion assay to visualize the pericellular coat on WT and Has1/3  fibroblasts [51]. Cells were labeled with calcein to delineate the cell bodies. The HA glycocalyx is indicated between the white and yellow lines. (b) Western blot of protein from WT or Has1/3  fibroblasts, probed with an antibody to type 1 collagen. GAPDH, loading control. (c) Quantification of protein band intensities from two independent western analysis experiments, performed under the conditions shown in panel (b) and normalized to GAPDH. White bars, WT fibroblasts. Gray bars, Has1/3  fibroblasts. Error bars, mean ± half-range.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Skin fibroblasts with a larger HA glycocalyx are more responsive to TGF-β and produce more collagen when cultured in a high glucose medium. Skin fibroblasts from either wild type (WT) or Has1/3 mice were cultured in normal glucose (1 g/L) or in high glucose (4.5 g/L) in the absence or presence of TGF-β1 (2 ng/mL) in DMEM media with 1% FBS for 48 hours. (a) Erythrocyte exclusion assay to visualize the pericellular coat on WT and Has1/3 fibroblasts [51]. Cells were labeled with calcein to delineate the cell bodies. The HA glycocalyx is indicated between the white and yellow lines. (b) Western blot of protein from WT or Has1/3 fibroblasts, probed with an antibody to type 1 collagen. GAPDH, loading control. (c) Quantification of protein band intensities from two independent western analysis experiments, performed under the conditions shown in panel (b) and normalized to GAPDH. White bars, WT fibroblasts. Gray bars, Has1/3 fibroblasts. Error bars, mean ± half-range.
Mentions: HA biology can be surprisingly cell-specific. Thus, while hyperglycemia causes problems in dermal microvessels by reducing HA in the EC glycocalyx, hyperglycemia affects dermal mesenchymal cells by increasing their HA glycocalyces. Work from the Tammi group showed that, in vascular smooth muscle cells (SMCs), high glucose promotes HA synthesis and HAS gene expression but impairs vascular SMC function as reflected by a reduced ability to contract collagen gels; this offers a potential mechanism whereby hyperglycemia could disturb vascular remodeling and contribute to arteriosclerosis [71]. Vigetti et al. showed that HMW-HA can protect human aortic SMCs against apoptosis induced by 4-methylumbelliferone (an HA synthesis inhibitor), suggesting that higher amounts of HA associated with SMCs increase their survival and might favor accumulation of SMCs in the vessel wall [72]. A similar relationship in which higher HA production appears to be protective against apoptosis was demonstrated in our studies of dermal fibroblasts [51]. Using HAS1/HAS3 double-knockout mice [51], we showed that fibroblasts compensate for the loss of HAS1 and HAS3 by overexpressing HAS2, resulting in an increase in HAS2 activity and synthesis of an enlarged HA glycocalyx relative to normal fibroblasts (Figure 2(a)). When exposed to apoptosis-inducing stress such as serum starvation, the HAS1/3 cells were less likely to die [51].

Bottom Line: Ulcers and chronic wounds are a particularly common problem in diabetics and are associated with hyperglycemia.In this targeted review, we summarize evidence suggesting that defective wound healing in diabetics is causally linked, at least in part, to hyperglycemia-induced changes in the status of hyaluronan (HA) that resides in the pericellular coat (glycocalyx) of endothelial cells of small cutaneous blood vessels.Possible roles of newly recognized, cross-linked forms of HA, and interactions of a major HA receptor (CD44) with cytokine/growth factor receptors during hyperglycemia, are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Ulcers and chronic wounds are a particularly common problem in diabetics and are associated with hyperglycemia. In this targeted review, we summarize evidence suggesting that defective wound healing in diabetics is causally linked, at least in part, to hyperglycemia-induced changes in the status of hyaluronan (HA) that resides in the pericellular coat (glycocalyx) of endothelial cells of small cutaneous blood vessels. Potential mechanisms through which exposure to high glucose levels causes a loss of the glycocalyx on the endothelium and accelerates the recruitment of leukocytes, creating a proinflammatory environment, are discussed in detail. Hyperglycemia also affects other cells in the immediate perivascular area, including pericytes and smooth muscle cells, through exposure to increased cytokine levels and through glucose elevations in the interstitial fluid. Possible roles of newly recognized, cross-linked forms of HA, and interactions of a major HA receptor (CD44) with cytokine/growth factor receptors during hyperglycemia, are also discussed.

No MeSH data available.


Related in: MedlinePlus