| Abstract: |
Prostaglandin transporter (PGT) mediates prostaglandin (PG) catabolism and PG signal termination. The prostanoid PGE 2, which induces angiogenesis and vasodilation, is diminished in diabetic skin, suggesting that PGT up-regulation could be important in wound healing deficiency, typified by diabetic foot ulcer. We hypothesized that up-regulation of PGT in hyperglycemia could contribute to weakened PGE 2 signaling, leading to impaired angiogenesis and wound healing. In human dermal microvascular endothelial cells (HDMECs), exposure to hyperglycemia increased PGT expression and activity up to threefold, accompanied by reduced levels of PGE 2. Hyperglycemia reduced HDMEC migration by 50% and abolished tube formation. Deficits in PGE 2 expression, HDMEC migration, and tube formation could be corrected by treatment with the PGT inhibitor T26A, consistent with the idea that PGT hyperactivity is responsible for impairments in angiogenesis mediated by PG signaling. In vivo, PGT expression was profoundly induced in diabetes and by wounding, correlating with diminished levels of proangiogenic factors PGE 2 and VEGF in cutaneous wounds of diabetic mice. Pharmacological inhibition of PGT corrected these deficits. PGT inhibition shortened cutaneous wound closure time in diabetic mice from 22 to 16 days. This effect was associated with increased proliferation, re-epithelialization, neovascularization, and blood flow. These data provide evidence that hyperglycemia enhances PGT expression and activity, leading to diminished angiogenic signaling, a possible key mechanism underlying defective wound healing in diabetes. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
| Keywords: |
signal transduction; vasculotropin; controlled study; vascular endothelial growth factor a; unclassified drug; human cell; nonhuman; cell proliferation; mouse; animals; mice; animal tissue; cells, cultured; animal experiment; animal model; in vivo study; angiogenesis; neovascularization, pathologic; mice, inbred c57bl; hyperglycemia; skin; wound healing; endothelium, vascular; prostaglandin e2; diabetes mellitus; cell migration; cell movement; epithelial cells; epithelization; up-regulation; blood flow; wound closure; regional blood flow; receptor upregulation; dinoprostone; organic anion transporters; diabetes mellitus, experimental; fatty acid transporter; prostaglandin inhibitor; prostaglandin transporter; t26a; microvascular endothelial cell
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