Cytochrome P450-derived epoxyeicosatrienoic acids accelerate wound epithelialization and neovascularization in the hairless mouse ear wound model
Cytochrome P450-derived epoxyeicosatrienoic acids accelerate wound epithelialization and neovascularization in the hairless mouse ear wound model
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DOI：
10.1007/s00423-011-0838-z
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发表时间：
2011-12-01
影响因子：
2.3
通讯作者：
Frank, Johannes
中科院分区：
文献类型：
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作者：
Sander, Anna Lena;Jakob, Heike;Frank, Johannes
目的环氧二十碳三烯酸(EETs)在体外可调节细胞增殖和血管生成。EETs的组织水平受产生它们的细胞色素P450(CYP)环氧合酶以及将它们代谢成活性较低的二醇的可溶性环氧化物水解酶的调节。本研究的目的是确定局部应用EETs(11，12-和14，15-EETs)和选择性sEH抑制剂trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic酸(t-AUCB)对体内创面愈合的影响。每隔一天使用活体内显微镜和计算机平面测量仪直接观察和测量伤口上皮化情况，直到愈合完成。结果EETs和t-AUCB分别在创面第2、4、13天通过协同上调SDF1α和血管新生血管生成促进创面上皮化和新生血管形成。结论外源性CYP来源的EETs和sEH抑制可显著促进未受损愈合创面上皮化和新生血管形成。鉴于低氧可诱导细胞色素P450的表达，进而导致EET依赖的血管生成，EETs和sEHIs为缺血性不可愈合创面提供了一种有希望的新的治疗方法。
Purpose Epoxyeicosatrienoic acids (EETs) are known to modulate proliferation and angiogenesis in vitro. Tissue levels of EETs are regulated by the cytochrome P450 (CYP) epoxygenases that generate them as well as by the soluble epoxide hydrolase metabolizes them to their less active diols. The aim of this study was to determine the effect of locally administered EETs (11,12- and 14,15-EETs) and the selective sEH inhibitor (sEHI) trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on wound healing in vivo.Methods Standardized full thickness dermal wounds were created on the dorsum of hairless mouse ears. Wound epithelialization was directly viewed and measured using intravitalmicroscopy and computerized planimetry every second day until healing was complete. Wound sections were analyzed by immunostaining for endothelial lineage marker CD31, vascular endothelial growth factor (VEGF), and angiogenic cytokine stromal cell-derived factor (SDF) 1 alpha on days 2, 4, and 13.Results Treatment with EETs and t-AUCB, respectively, significantly accelerated wound epithelialization and neovascularization by synergistic upregulation of SDF1 alpha and VEGF in vivo.Conclusions These findings demonstrated that exogenous CYP-derived EETs and globally decreased EET hydrolysis by sEH inhibition significantly accelerated wound epithelialization and neovascularization in unimpaired healing wounds. Given that hypoxia induces CYP expression and subsequently EET-dependent angiogenesis, EETs and sEHIs provide a promising new class of therapeutics for ischemic non-healing wounds.