Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats.
Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats.
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DOI：
10.1371/journal.pone.0133615
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chi Y
中科院分区：
文献类型：
--
作者：
Liu Z;Benard O;Syeda MM;Schuster VL;Chi Y
由动脉血流减少和局部血管化缺陷引起的外周缺血是糖尿病伤口愈合受损的主要原因之一。血管舒张性前列腺素（PGs），包括PGE2和PGI2，调节外周组织中的血流。PG还通过诱导血管内皮生长因子刺激血管生成。然而，糖尿病患者的PG水平降低主要是由于降解增强。我们假设，抑制前列腺素转运蛋白（PGT）（SLCO 2A1），介导前列腺素的降解，将增加血流量和刺激血管形成，从而减轻外周缺血和加速糖尿病伤口愈合。在这里，我们报告，抑制PGT与静脉注射PGT抑制剂，T26A，增加血流量在缺血后肢在非糖尿病大鼠和链脲佐菌素诱导的糖尿病大鼠。全身或与局部结合，T26A加速皮肤伤口的闭合。免疫组织化学检查显示，PGT的抑制增强血管形成（由CD34+细胞形成的大量血管标记），并加速皮肤伤口的再上皮化。在培养的原代人骨髓CD34+细胞和人表皮角质形成细胞（HEK）中，抑制或沉默PGT增加了两种细胞系的迁移。因此，PGT直接调节内皮祖细胞（EPC）和HEK的动员，这可能有助于PGT介导的血管化和上皮再形成。在分子水平上，PGT的全身抑制提高了循环PGE2。总之，我们的数据表明，PGT调节动脉血流量，动员内皮祖细胞和HEK，血管化和上皮化伤口愈合通过调节血管扩张和促血管生成的PG。
Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs), including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT) (SLCO2A1), which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells), and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs) either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs) and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs.