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.

Topical Prostaglandin E Analog Restores Defective Dendritic Cell–Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice

“…We did not detect any differences in the production of prostacyclin (another prostanoid that exerts immunoregulatory properties) or PGE 2 metabolites in the skin of diabetic mice infected with MRSA. These data contrast with previous reports that showed that hyperglycemia enhances prostaglandin degradation by increasing the expression and activity of PGE 2 transporter, leading to diminished PGE 2 levels and angiogenic signaling in diabetic skin (15). The reasons for such discrepancies are unknown, but it could be due to differences in animal models, cells involved in the inflammatory response during angiogenesis, and infection.…”

“…As well, during wound healing, diabetic mouse skin exhibits a decreased capacity to produce PGE 2 (15). Moreover, diminished production of COX products of arachidonic acid metabolism have been described as an abnormality of polymorphonuclear leukocytes in diabetes (33).…”

“…Microsomal PGE synthase 1 is induced during the inflammatory response that acts mainly downstream of COX-2 to convert PGH 2 to PGE 2 . The levels of PGE 2 are regulated by the local balance between the COX-2–driven synthesis and 15-hydroxyprostaglandin dehydrogenase–mediated degradation of PGE 2 or the actions of prostaglandin transporters (15). PGE 2 acts through four G-protein–coupled receptors, designated EP1–EP4, which display different tissue distributions and deliver distinct intracellular signals (16).…”

Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer

“…However, in the environment of chronic inflammation, PGT is expressed at lower levels than in normal tissue (53). It is unclear whether the reduction of PGT expression causes chronic inflammation by decreasing PGE 2 clearance, or is a result of the sustained pro-inflammatory environment.…”

A Novel Long-Acting Prostacyclin Agonist (ONO-1301) With an Angiogenic Effect: Promoting Synthesis of Hepatocyte Growth Factor and Increasing Cyclic AMP Concentration via IP-Receptor Signaling

“…Previous studies have reported that PGE 2 regulates angiogenesis (17,18). Its receptor is EP3 (19,20), and suppression of cAMP is caused by EP3 activation (21,22).…”