Downregulation of the proangiogenic prostaglandin E receptor EP3 and reduced angiogenesis in a mouse model of diabetes mellitus.
Downregulation of the proangiogenic prostaglandin E receptor EP3 and reduced angiogenesis in a mouse model of diabetes mellitus.
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DOI：
10.1016/j.biopha.2014.10.022
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发表时间：
2014-10
期刊：
影响因子：
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通讯作者：
Kazuhito Oba;K. Hosono;H. Amano;Shin-ichiro Okizaki;Yoshiya Ito;M. Shichiri;M. Majima
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文献类型：
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作者：
Kazuhito Oba;K. Hosono;H. Amano;Shin-ichiro Okizaki;Yoshiya Ito;M. Shichiri;M. Majima
血管并发症，如足部溃疡是糖尿病（DM）的标志，但血管功能障碍的分子机制仍不清楚。在此，我们表明，血管生成，这是必不可少的愈合溃疡，是抑制聚氨酯海绵植入物在小鼠糖尿病和减少促血管生成的信号。通过腹腔注射链脲佐菌素（100 mg/kg）在雄性C57 BL/6小鼠中诱导DM。将聚氨酯海绵片植入小鼠背部皮下组织，分析海绵肉芽组织中血管生成及相关因子的表达。血小板内皮细胞粘附分子-1（PECAM-1）阳性血管结构的密度和海绵肉芽组织中的PECAM-1表达在对照小鼠中随时间增加，在糖尿病小鼠中减少。糖尿病小鼠中的减少伴随着诱导型环氧合酶-2和微粒体前列腺素E合酶-1的表达减少。前列腺素E受体亚型EP 3在糖尿病小鼠的海绵肉芽组织中下调，而EP 1、EP 2和EP 4则没有。促血管生成生长因子血管内皮生长因子（VEGF）-A和趋化因子基质细胞衍生因子-1（SDF-1）的表达在糖尿病小鼠中均降低。用EP 3的选择性激动剂ONO-AE 248（30 nmol/部位/天，局部注射）治疗糖尿病小鼠，逆转了糖尿病小鼠中血管生成的抑制。这些结果表明，在VEGF和SDF-1表达减少的糖尿病小鼠中，促血管生成的EP 3信号传导受到抑制。在DM小鼠海绵植入模型中，刺激EP 3信号恢复血管生成。这表明，局部应用EP 3激动剂可能是治疗糖尿病患者足部溃疡的一种新策略。
Vascular complications such as foot ulcers are a hallmark of diabetes mellitus (DM), although the molecular mechanisms that underlie vascular dysfunction remain unclear. Herein, we show that angiogenesis, which is indispensable to the healing of ulcers, is suppressed in polyurethane sponge implants in mice with DM and reduced proangiogenic signaling. DM was induced in male C57BL/6 mice by intraperitoneal injection of streptozotocin (100 mg/kg). Polyurethane sponge disks were implanted into subcutaneous tissues on the backs of mice, and angiogenesis and expression of related factors were analyzed in sponge granulation tissues. Densities of platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive vascular structures and PECAM-1 expression in sponge granulation tissues were increased over time in control mice and reduced in diabetic mice. The reductions in diabetic mice were accompanied by reduced expression of inducible cyclo-oxygenase-2 and microsomal prostaglandin E synthase-1. The prostaglandin E receptor subtype EP3 was downregulated in sponge granulation tissues in diabetic mice, whereas EP1, EP2, and EP4 were not. The expression of the proangiogenic growth factor vascular endothelial growth factor (VEGF)-A and the chemokine stromal cell-derived factor-1 (SDF-1) were both reduced in diabetic mice. Treatment of diabetic mice with a selective agonist of EP3, ONO-AE 248 (30 nmol/site/day, topical injection), reversed suppression of angiogenesis in diabetic mice. These results indicate that proangiogenic EP3 signaling is suppressed in diabetic mice with reduced expression of VEGF and SDF-1. Stimulation of EP3 signaling restored angiogenesis in a sponge implant model in mice with DM. This suggests that topical application of an EP3 agonist could be a novel strategy to treat foot ulcers in patients with DM.