IGF1 is Developmentally Regulated in the Neonatal Intestine and Protects Neonatal Mice against Necrotizing Enterocolitis by Preserving the VEGF/VEGFR2 Signaling Pathway in an Animal Model

Abstract

Necrotizing enterocolitis (NEC) is a common gastrointestinal disease affecting premature infants and associated with high morbidity and mortality. Its pathogenesis remains poorly understood. Decreased levels of serum IGF1 has been shown to be associated with a higher incidence of NEC in premature infants. We previously found that neonatal pups are most susceptible to NEC in the first few days of life. Here we hypothesize that IGF‐1 levels are low during the first days of life, and that exogenous IGF1 is protective against NEC via promoting intestinal VEGF/VEGFR2 signaling. To test our hypotheses, we first assessed the developmental expression of IGF1 in the serum and the intestinal tissues in neonatal mice during the first 3 weeks of life, and determined whether exposure to a NEC protocol affects serum and intestinal IGF1 levels. Secondly, we examined whether exogenous IGF1 protects against NEC and affects intestinal VEGF production both in vivo and in vitro. We found that: Serum IGF1 level is low during the first 2 days of life, and gradually increases over 3 weeks. In contrast, IGF1 expression in the intestinal tissue is low at birth, peaks between 3 days and 2 weeks of age, before decreasing to low level by 3 weeks. In pups exposed to a NEC protocol compared to DF controls, serum IGF1concentration was significantly decreased at 12 hours and 24 hours (by 35%, p<0.05; and 59%, p<0.0001 respectively ). Intestinal tissue IGF1 expression decreased as early as 6 hours into NEC, which occurred before the decrease in serum IGF1. Exogenous IGF1 treatment decreased mortality in pups exposed to NEC protocol (41% vs. 68%, p<0.05), decreased the incidence of severe NEC (histological score ≥ 2) (χ2=4.03, p<0.05) and increased intestinal VEGF/VEGFR2 protein expression. Neonatal intestinal endothelial cells treated with IGF1 in vitro had increased VEGF mRNA transcription and protein expression (p<0.05 for both). We conclude that the beneficial effect of IGF1 on experimental NEC may be due to protection of small intestinal microvasculature development through preserving VEGF/VEGFR2 signaling pathway.Support or Funding InformationShireThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.