Neonatal GI Physiology & NEC
Neonatal GI Physiology & NEC 1: GI Health and NEC Complications
Marina Mitrou, MD (she/her/hers)
Resident physician
State University of New York Downstate Medical Center College of Medicine
New York, New York, United States
Gut angiogenesis is important vital functions such as nutrient uptake, digestion, barrier function, and protection from infections. Vascular endothelial growth factor (VEGF) plays a key role in normal and aberrant angiogenesis and is highly upregulated by hypoxia via hypoxia-inducible factor (HIF)1α. Maldevelopment of the intestinal mucosal microvasculature plays an important role in necrotizing enterocolitis (NEC) pathogenesis. Extremely low gestational age neonates experience frequent intermittent hypoxia (IH) episodes during oxygen therapy, which can adversely affect immature gut angiogenesis. Defects in intestinal VEGF/VEGFR2 signaling may increase the susceptibility to NEC.
Objective: To examine the hypotheses that: 1) increasing IH episodes with recovery in hyperoxia between episodes induces aberrant angiogenesis in the large intestines; and 2) there is a number of daily IH episodes that induce large bowel injury.
Design/Methods: Neonatal rats were exposed to hyperoxia (50% O2) with 2, 4, 6, 8, 10, or 12 IH (12% O2) episodes per day (EPD) from birth (P0) to postnatal day 7 (P7; 7D) or P0-P14 (14D). Pups were studied at P7 or P14 to determine immediate effects, or allowed to recover in room air (RA) until P21 (re-oxygenation). P7 animals remained in RA for 14 days (P21-7D), and P14 animals for 7 days (P21-14D). Animals exposed to 50% O2 only from P0 to P21 served as hyperoxia controls, and animals raised in RA from P7 to P21 served as normoxia controls. Large intestines were assessed for histopathology, apoptosis, and biomarkers of angiogenesis.
Results: IH resulted in significant histopathological changes including villous atrophy, denuded villi, mucosal and intestinal wall injury, and hemorrhage, beginning with 2 IH EPD. In the 7-day groups, HIF1α, peaked with 6 EPD, while VEGF and sVEGFR-1 progressively increased to peak with 12 EPD. In the 14-day groups, HIF1α and soluble VEGFR-1 increased from 2 EPD to peak at 12 EPD, while VEGF increased only at 10 and 12 EPD, and remained elevated despite recovery in RA.
Conclusion(s): IH causes significant damage to the immature gut coincident with alterations in normal angiogenesis biomarkers. These aberrant effects begin with 2 IH episodes and escalate as the number increases, suggesting that close monitoring of IH episodes in preterm infants is warranted to prevent bowel injury.