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

Mahrukh M. Syeda, Xiaohong Jing, Raihan H. Mirza, Hong Yu, Rani S. Sellers, Yuling Chi

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)334-346
Number of pages13
JournalAmerican Journal of Pathology
Volume181
Issue number1
DOIs
Publication statusPublished - Jul 1 2012

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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