Endogenous VEGF deficiency causes intestinal microcirculatory dysfunction in a model of neonatal necrotizing enterocolitis (832.1)

Abstract

Ischemic necrosis is a feature of necrotizing enterocolitis (NEC). We have previously found that VEGF is decreased in a neonatal mouse model of NEC. Here, we hypothesized that, in NEC, VEGF deficiency causes altered neonatal intestinal microvasculature and impaired microcirculation leading to NEC development. To test this hypothesis, neonatal pups were injected intraperitoneally with SU5416, a VEGF receptor kinase inhibitor prior to exposure to a NEC protocol. The intestinal mucosal microvasculature morphology was assessed by imaging after intracardiac dye injection. Endothelial (CD31+) cells were quantified by flow cytometry analysis following collagenase digestion of intestinal tissues. We found that: 1) Intestinal vascular networks were decreased in pups exposed to the NEC protocol for 48 hours compared to controls, and further decreased in pups treated with VEGF inhibitor; 2) The percentage of CD31+ cells in the CD45‐ Epcam‐ population was decreased in NEC small intestines (1.20%) vs. dam‐fed controls (4.64%), and further decreased when VEGF pathway was blocked (0.37%, p<0.05 vs dam‐fed). Pups exposed to the NEC protocol treated with VEGF inhibitor had increased incidence of severe NEC (score蠅2), compared to controls (18/29 vs 8/32, χ2=7.1, p<0.01) and had increased mortality. In conclusion, we found that inhibition of endogenous VEGF causes intestinal microcirculatory dysfunction and facilitates the development of neonatal NEC.. Grant Funding Source: Supported by a Thrasher Foundation Grant