Prostaglandin transporter modulates wound healing in diabetes by regulating prostaglandin-induced angiogenesis.

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.

• Authors: Mahrukh M Syeda, Xiaohong Jing, Raihan H Mirza, Hong Yu, Rani S Sellers, Yuling Chi
• Journal: The American journal of pathology (Am J Pathol) Vol. 181 Issue 1 Pg. 334-46 (Jul 2012) ISSN: 1525-2191 [Electronic] United States
• PMID: 22609345 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Organic Anion Transporters
• SLCO2A1 protein, human
• Slco2a1 protein, mouse
• Vascular Endothelial Growth Factor A
• Dinoprostone

Topics

• Animals
• Cell Movement (physiology)
• Cells, Cultured
• Diabetes Mellitus, Experimental (metabolism, physiopathology)
• Dinoprostone (metabolism)
• Endothelium, Vascular (metabolism)
• Epithelial Cells (physiology)
• Humans
• Hyperglycemia (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (physiopathology)
• Organic Anion Transporters (antagonists & inhibitors, metabolism, physiology)
• Regional Blood Flow (physiology)
• Skin (blood supply, injuries, metabolism)
• Up-Regulation (physiology)
• Vascular Endothelial Growth Factor A (biosynthesis)
• Wound Healing (physiology)