Division of Neonatology, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
Center for Intestinal and Liver Inflammation Research, Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois.
Pediatr Res. 2018 Feb;83(2):545-553. doi: 10.1038/pr.2017.219. Epub 2017 Oct 25.
BackgroundNecrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by intestinal necrosis. Hypoxia-inducible factor-1α (HIF-1α) has 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 vascular endothelial growth factor (VEGF) signaling.MethodsTo assess the role of PHD inhibition in a neonatal mouse NEC model, we administered dimethyloxalylglycine (DMOG) or vehicle to pups before or during the NEC protocol, and determined mortality and incidence of severe intestinal injury. We assessed intestinal VEGF by western blot analysis and quantified endothelial cell and epithelial cell proliferation following immunofluorescence.ResultsDMOG 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.ConclusionDMOG 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 VEGFR2 dependent improvement of the intestinal microvasculature.
坏死性小肠结肠炎（NEC）是一种以肠道坏死为特征的毁灭性新生儿疾病。缺氧诱导因子-1α（HIF-1α）在细胞氧平衡中起着关键作用。在这里，我们假设脯氨酰羟化酶（PHD）抑制，稳定 HIF-1α，通过血管内皮生长因子（VEGF）信号通路促进肠内皮细胞增殖和改善肠微血管完整性，从而预防 NEC。
为了评估 PHD 抑制在新生小鼠 NEC 模型中的作用，我们在 NEC 方案之前或期间给予 DMOG 或载体，并确定死亡率和严重肠道损伤的发生率。我们通过 Western blot 分析评估肠道 VEGF，并通过免疫荧光定量内皮细胞和上皮细胞增殖。
DMOG 降低了死亡率和严重 NEC 的发生率，增加了肠道 VEGF 的表达，并增加了实验性 NEC 中肠绒毛内皮和上皮细胞的增殖。抑制 VEGFR2 信号通路消除了 DMOG 对肠道损伤严重程度、存活率和内皮细胞增殖的保护作用，而保留了 DMOG 对肠上皮细胞增殖的保护作用。
DMOG 通过 VEGFR2 依赖性方式上调肠道 VEGF，促进内皮细胞增殖，从而预防实验性 NEC 中的肠道损伤和死亡。DMOG 对新生儿肠道黏膜的保护作用可能是通过 VEGFR2 依赖性改善肠道微血管来介导的。
