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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 biopsies from a wound edge at 24 h after wounding. Specimens from (a) normal mice (wild type) or (b) knockout mice lacking the genes for HAS1 and HAS3 (Has1/3 ) were stained with an HA binding probe to visualize HA (green) and an anti-myeloperoxidase antibody to visualize neutrophils (red). Note the marked loss of HA and increase in neutrophils extravasating from the blood vessel (BV) in the HAS1/3 deficient skin. Bar, 50 μm. From [50], used with permission.
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fig1: Skin biopsies from a wound edge at 24 h after wounding. Specimens from (a) normal mice (wild type) or (b) knockout mice lacking the genes for HAS1 and HAS3 (Has1/3 ) were stained with an HA binding probe to visualize HA (green) and an anti-myeloperoxidase antibody to visualize neutrophils (red). Note the marked loss of HA and increase in neutrophils extravasating from the blood vessel (BV) in the HAS1/3 deficient skin. Bar, 50 μm. From [50], used with permission.

Mentions: In our lab, we have utilized HAS1/HAS3 double-knockout (HAS1/3 ) mice as another model in which to study effects of altered HA upon leukocyte recruitment from the vasculature. In mammals, three HA synthase enzymes (HAS1, HAS2, and HAS3) are normally expressed. Deletion of the Has2 gene is embryonic lethal in mice, due to defects in cardiac development; however, mice lacking Has1 and/or Has3 genes are normal and viable [50]. Interestingly, cutaneous wound healing is abnormal in the HAS1/3 mice and is associated with increased wound inflammation due to enhanced recruitment of neutrophils at day 1 and macrophages at day 3, emanating from the cutaneous microvasculature at the wound site [50]. Compared to the normal amounts of HA in the blood vessels and surrounding dermis in wild type mouse skin (Figure 1(a)), reduced amounts of HA in the dermis and blood vessel walls (including HA associated with the EC) are observed in HAS1/3 mice in the same vessels at which large numbers of neutrophils appear to be recruited (Figure 1(b)). Further experiments are ongoing in our laboratory to test the hypothesis that reduced HA in the endothelial glycocalyx allows leukocytes greater access to adhesion molecules such as V-CAM and I-CAM on the endothelial surface.


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 biopsies from a wound edge at 24 h after wounding. Specimens from (a) normal mice (wild type) or (b) knockout mice lacking the genes for HAS1 and HAS3 (Has1/3 ) were stained with an HA binding probe to visualize HA (green) and an anti-myeloperoxidase antibody to visualize neutrophils (red). Note the marked loss of HA and increase in neutrophils extravasating from the blood vessel (BV) in the HAS1/3 deficient skin. Bar, 50 μm. From [50], used with permission.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581551&req=5

fig1: Skin biopsies from a wound edge at 24 h after wounding. Specimens from (a) normal mice (wild type) or (b) knockout mice lacking the genes for HAS1 and HAS3 (Has1/3 ) were stained with an HA binding probe to visualize HA (green) and an anti-myeloperoxidase antibody to visualize neutrophils (red). Note the marked loss of HA and increase in neutrophils extravasating from the blood vessel (BV) in the HAS1/3 deficient skin. Bar, 50 μm. From [50], used with permission.
Mentions: In our lab, we have utilized HAS1/HAS3 double-knockout (HAS1/3 ) mice as another model in which to study effects of altered HA upon leukocyte recruitment from the vasculature. In mammals, three HA synthase enzymes (HAS1, HAS2, and HAS3) are normally expressed. Deletion of the Has2 gene is embryonic lethal in mice, due to defects in cardiac development; however, mice lacking Has1 and/or Has3 genes are normal and viable [50]. Interestingly, cutaneous wound healing is abnormal in the HAS1/3 mice and is associated with increased wound inflammation due to enhanced recruitment of neutrophils at day 1 and macrophages at day 3, emanating from the cutaneous microvasculature at the wound site [50]. Compared to the normal amounts of HA in the blood vessels and surrounding dermis in wild type mouse skin (Figure 1(a)), reduced amounts of HA in the dermis and blood vessel walls (including HA associated with the EC) are observed in HAS1/3 mice in the same vessels at which large numbers of neutrophils appear to be recruited (Figure 1(b)). Further experiments are ongoing in our laboratory to test the hypothesis that reduced HA in the endothelial glycocalyx allows leukocytes greater access to adhesion molecules such as V-CAM and I-CAM on the endothelial surface.

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