Intestinal Vascular Endothelial Growth Factor Is Decreased in Necrotizing Enterocolitis

Abstract

Background: Decreased intestinal perfusion may contribute to the development of necrotizing enterocolitis (NEC). Vascular endothelial growth factor (VEGF) is an angiogenic protein necessary for the development and maintenance of capillary networks. Whether VEGF is dysregulated in NEC remains unknown. Objectives: The objective of this study was to determine whether intestinal VEGF expression is altered in a neonatal mouse model of NEC and in human NEC patients. Methods: We first assessed changes of intestinal VEGF mRNA and protein in a neonatal mouse NEC model before significant injury occurs. We then examined whether exposure to formula feeding, bacterial inoculation, cold stress and/or intermittent hypoxia affected intestinal VEGF expression. Last, we visualized VEGF protein in intestinal tissues of murine and human NEC and control cases by immunohistochemistry. Results: Intestinal VEGF protein and mRNA were significantly decreased in pups exposed to the NEC protocol compared to controls. Hypoxia, cold stress and commensal bacteria, when administered together, significantly downregulated intestinal VEGF expression, while they had no significant effect when given alone. VEGF was localized to a few single intestinal epithelial cells and some cells of the lamina propria and myenteric plexus. VEGF staining was decreased in murine and human NEC intestines when compared to control tissues. Conclusion: Intestinal VEGF protein is reduced in human and experimental NEC. Decreased VEGF production might contribute to NEC pathogenesis.

Lack of VEGFR2 signaling causes maldevelopment of the intestinal microvasculature and facilitates necrotizing enterocolitis in neonatal mice

“…Recently, we found that VEGF-A is decreased in the intestinal samples of human NEC (36). Furthermore, using a mouse NEC model, we show here that VEGF-A (36) and VEGFR2 proteins are decreased in the intestine in the early stages of NEC development, before evidence of tissue necrosis, compared with DF controls.…”

“…We previously found that VEGF-A is localized mainly to a few single intestinal epithelial cells and to some cells of the lamina propria and myenteric plexus (36). In this study, we further characterize the cells producing VEGF-A in the intestinal mucosa.…”

“…We previously showed that VEGF-A expression is decreased in intestinal surgical samples of patients with NEC compared with control tissue samples obtained from patients with other diseases such as ileal atresia, intestinal reanastomosis, duplication cyst, or Hirschsprung disease (36). Furthermore, we found that VEGF-A protein is decreased in a neonatal mouse NEC model (36).…”

“…Furthermore, we found that VEGF-A protein is decreased in a neonatal mouse NEC model (36). Therefore, we hypothesize that VEGF-A/VEGFR2 signaling promotes perinatal intestinal mucosal microvascular development and plays a protective role in neonatal NEC.…”

Risk of Necrotizing Enterocolitis Associated With the Single Nucleotide Polymorphisms VEGF C-2578A, IL-18 C-607A, and IL-4 Receptor α-Chain A-1902G: A Validation Study in a Prospective Multicenter Cohort

“…It is suggested that VEGF-mediated alterations of the intestinal mucosal microvasculature play an important role in NEC pathogenesis (9,13,24,25). In fact, intestinal VEGF protein expression is reduced in human and experimental NEC (9,26). The VEGF gene is highly polymorphic, especially in the promoter, 5 ′untranslated and 3 ′ -untranslated regions (27).…”