Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: role of VEGF signaling.
Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: role of VEGF signaling.
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DOI：
10.1038/pr.2017.219
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发表时间：
2018-03
影响因子：
3.6
通讯作者：
De Plaen IG
中科院分区：
文献类型：
--
作者：
Bowker RM;Yan X;Managlia E;Liu SXL;Marek C;Tan XD;De Plaen IG
NEC是一种以肠坏死为特征的毁灭性新生儿疾病。缺氧诱导因子-1 α（Hypoxia inducible factor-1α，HIF-1α）在维持细胞氧平衡中起重要作用。在这里，我们假设脯氨酰羟化酶（PHD）抑制，稳定HIF-1α，通过促进肠内皮细胞增殖和改善肠微血管的完整性，通过VEGF信号传导，防止NEC。为了评估PHD抑制在新生小鼠NEC模型中的作用，我们在NEC方案之前或期间向幼仔施用DMOG或媒介物，并测定死亡率和严重肠损伤的发生率。我们通过免疫印迹法评估肠VEGF，并在免疫荧光后定量内皮细胞和上皮细胞增殖。在实验性NEC中，DMOG降低死亡率和严重NEC的发生率，增加肠VEGF表达，并增加肠绒毛内皮细胞和上皮细胞增殖。抑制VEGFR 2信号传导消除了DMOG对肠损伤严重程度、存活率和内皮细胞增殖的保护作用，同时保留了DMOG对肠上皮细胞增殖的保护作用。DMOG上调肠VEGF，促进内皮细胞增殖，并以VEGFR 2依赖性方式保护实验性NEC免受肠损伤和死亡。DMOG对新生儿肠粘膜的保护作用可能是通过VEGFR-2依赖性改善肠道微血管来介导的。
NEC is a devastating neonatal disease characterized by intestinal necrosis. Hypoxia inducible factor-1α (HIF-1α) plays a critical role in cellular oxygen homeostasis. Here, we hypothesized that prolyl hydroxylase (PHD) inhibition, which stabilizes HIF-1α, protects against NEC by promoting intestinal endothelial cell proliferation and improving intestinal microvascular integrity via VEGF signaling. To assess the role of PHD inhibition in a neonatal mouse NEC model, we administered DMOG or vehicle to pups prior to or during the NEC protocol, and determined mortality and incidence of severe intestinal injury. We assessed intestinal VEGF by Western blot and quantified endothelial cell and epithelial cell proliferation following immunofluorescence. DMOG decreased mortality and incidence of severe NEC, increased intestinal VEGF expression, and increased intestinal villus endothelial and epithelial cell proliferation in experimental NEC. Inhibiting VEGFR2 signaling eliminated DMOG’s protective effect on intestinal injury severity, survival, and endothelial cell proliferation while sparing DMOG’s protective effect on intestinal epithelial cell proliferation. DMOG upregulates intestinal VEGF, promotes endothelial cell proliferation and protects against intestinal injury and mortality in experimental NEC in a VEGFR2-dependent manner. DMOG’s protective effect on the neonatal intestinal mucosa may be mediated via VEGFR-2 dependent improvement of the intestinal microvasculature.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1084/jem.20120690
发表时间：
2013-11-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Avraham-Davidi I;Yona S;Grunewald M;Landsman L;Cochain C;Silvestre JS;Mizrahi H;Faroja M;Strauss-Ayali D;Mack M;Jung S;Keshet E
通讯作者：
Keshet E
肠道血管内皮生长因子在坏死性小肠结肠炎中降低。
影响因子：
2.5
作者：
Sabnis A;Carrasco R;Liu SX;Yan X;Managlia E;Chou PM;Tan XD;De Plaen IG
通讯作者：
De Plaen IG
DOI：
10.1038/nrgastro.2010.39
发表时间：
2010-05
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1186/s40348-016-0030-1
发表时间：
2016-12
期刊：
Molecular and cellular pediatrics
影响因子：
--
作者：
Shah YM
通讯作者：
Shah YM