HIF-1α stabilization modified by glutaredoxin-1 is critical for intestinal angiogenesis in NEC pathogenesis

BackgroundHypoxia inducible factor (HIF-1) are essential in the pathogenesis of necrotizing enterocolitis (NEC), which is stabilized by Grx1 deletion. Until now, the mechanism of HIF-1 in the intestinal microcirculation in NEC is not well defined. We intend to investigate the role of HIF-1 in the development of NEC in regulating the microcirculation and the following vasodilatory signal, VEGF. Materials and methodsExperimental NEC was induced in full-term C57BL/6 mouse and Grx1-/- pups through the formula gavage and hypoxia technique. The HIF-1 signal was blocked utilizing the HIF-1 inhibitor, YC-1. Intestinal tissues were collected at predetermined time points for the assessment of intestinal microcirculation and the HIF-1 activity involved signal. ResultsWe found that NEC inducement impaired the intestinal microcirculation, but intestinal blood flow and capillary density were ameliorated in Grx1-/- mice, which was associated with the GSH-protein adducts of HIF-1 in the intestinal tissue. Grx1 ablation could also promote vascular endothelial growth factor (VEGFA) production in the intestinal tissue. This intestinal microvascular improvement was not found in the HIF-1 inhibited mice, suggesting the HIF-1 dependent manner for intestinal microcirculatory perfusion. ConclusionThe current data demonstrated that HIF-1 signaling is involved in the intestinal microvascular modification during the pathogenesis of NEC, suggesting that targeting with HIF-1 might be a promising strategy for NEC treatment.