Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality for premature infants. Common long-term complications are short gut syndrome and neurodevelopmental delay, which significantly impact the quality of life of these patients. In contrast to other neonatal diseases, no specific therapeutic intervention currently exists to prevent or treat NEC. We found novel evidence that an underdeveloped gut microvasculature plays a previously unrecognized but crucial role in NEC. Indeed, we show that the normal gut mucosal microvasculature undergoes significant development during the perinatal period, and that the fetal intestine expresses high levels of both vascular endothelial growth factor-A (VEGF), a key regulator of angiogenesis, and its receptor VEGFR2. Furthermore, defective VEGFR2 signaling promotes NEC in a neonatal mouse model. VEGFR2 controls the expression of FoxM1, a transcription factor regulating cell cycle progression, in neonatal intestinal endothelial cells (EndCs), and mice overexpressing FoxM1 are protected against NEC. Our preliminary data further suggest that in the neonatal intestine, vascular growth and EndC proliferation are supported by embryonic macrophages (eMf) via an insulin-like growth factor-1 (IGF-1)-dependent mechanism, with IGF-1 inducing VEGF expression and thereby protecting against NEC by promoting intestinal microvascular expansion. These data provide the basis for our overarching premise that, in premature infants, the oxygen-mediated downregulation of intestinal pro-angiogenic signaling pathways (such as VEGF/VEGFR2) due to birth occurs before the intestinal microvasculature sufficiently develops. Perinatal stresses (such as inflammation) reduce IGF-1 secretion by intestinal eMf, thereby decreasing EndC IGF-1-mediated VEGF production. The resultant decrease in VEGFR2 signaling impairs FoxM1-dependent EndC proliferation and subsequent vascular development. Therefore, the underdeveloped intestinal microvasculature, while sufficient for a ?sterile? fasted intestine, becomes inadequate to meet the metabolic demand of postnatal stresses such as enteral feeding and bacterial colonization, and this results in intestinal ischemia and necrosis. In this proposal, we will test the hypothesis that, in infants at high risk for NEC, lack of IGF-1 production by intestinal eMf decreases VEGFR2/FoxM1 signaling in EndCs, thus perturbing the normal development of intestinal mucosal capillaries during the perinatal period and making the intestine prone to NEC under perinatal stresses (e.g., inflammation, hypoxia, formula-feeding). We will address the following specific aims: 1) Determine how defective EndC VEGFR2 signaling promotes NEC. For this aim, we will utilize novel mice with endothelial cell-specific VEGFR2 deficiency or with endothelial cell-specific FoxM1 expression; 2) Define the cellular mechanisms by which eMf promote VEGFR2 signaling in neonatal intestinal EndCs and microvascular development to prevent NEC. In this aim, we will determine how eMf-derived IGF-1 promote endothelial cell signaling to protect against NEC. These studies will characterize the interaction between inflammation and gut microvasculature development in the pathogenesis of NEC and will provide a solid foundation for testing novel therapeutic strategies that can preserve local VEGFR2 signaling to prevent NEC.

Public Health Relevance

The proposed research on necrotizing enterocolitis (NEC) is very relevant to public health as NEC is a devastating intestinal disease of premature babies with great morbidity and mortality. Therefore understanding the underlying mechanisms of NEC will help define therapeutic strategies to prevent/treat the disease. This research uses genetically manipulated mice to study the intestinal microvasculature and VEGFR2, a protein receptor that promotes vessel growth, and to investigate their role in neonatal intestinal injury.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Greenwel, Patricia
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Children's Memorial Hospital (Chicago)
United States
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