Prostaglandin Transporter Modulates Wound Healing in Diabetes by Regulating Prostaglandin-Induced Angiogenesis
Prostaglandin Transporter Modulates Wound Healing in Diabetes by Regulating Prostaglandin-Induced Angiogenesis
复制标题
DOI：
10.1016/j.ajpath.2012.03.012
复制
发表时间：
2012-07-01
影响因子：
6
通讯作者：
Chi, Yuling
中科院分区：
文献类型：
--
作者：
Syeda, Mahrukh M.;Jing, Xiaohong;Chi, Yuling
前列腺素转运蛋白（PGT）介导前列腺素（PG）的催化和PG信号的终止。诱导血管生成和血管舒张的前列腺素PGE（2）在糖尿病皮肤中减少，表明PGT上调在伤口愈合缺陷中可能很重要，以糖尿病足溃疡为代表。我们假设高血糖时PGT的上调可能导致PGE（2）信号减弱，导致血管生成和伤口愈合受损。在人真皮微血管内皮细胞（HDMECs）中，暴露于高血糖使PGT表达和活性增加高达三倍，同时伴有PGE水平降低（2）。高血压使HDMEC迁移减少了50%，并消除了管形成。PGT抑制剂T26 A治疗可以纠正PGE（2）表达、HDMEC迁移和管形成的缺陷，这与PGT过度活跃导致PG信号介导的血管生成障碍的观点一致。在体内，PGT表达在糖尿病和创伤中被深刻地诱导，与糖尿病小鼠皮肤伤口中促血管生成因子PGE（2）和VEGF水平的降低相关。PGT的药理学抑制纠正了这些缺陷。PGT抑制剂使糖尿病小鼠皮肤伤口闭合时间从22天缩短至16天。这种效应与增殖、上皮再生、新血管形成和血流增加有关。这些数据提供的证据表明，高血糖症增强PGT的表达和活性，导致减少血管生成信号，一个可能的关键机制，糖尿病伤口愈合缺陷。(Am病理学杂志2012，181：334-346。http://dx.doi.org/10.1016/j.ajpath.2012.03.012)
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. (Am J Pathol 2012, 181: 334-346. http://dx.doi.org/10.1016/j.ajpath.2012.03.012)