# Role of the intestinal microvasculature in necrotizing enterocolitis

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $541,860

## Abstract

ABSTRACT
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 ...

## Key facts

- **NIH application ID:** 9869007
- **Project number:** 5R01DK116568-02
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Isabelle G De Plaen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $541,860
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869007

## Citation

> US National Institutes of Health, RePORTER application 9869007, Role of the intestinal microvasculature in necrotizing enterocolitis (5R01DK116568-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9869007. Licensed CC0.

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