Hypoxia-Inducible Factor 1α Stability Modified by Glutaredoxin-1 in Necrotizing Enterocolitis.

INTRODUCTION

Hypoxia-inducible factor (HIF) 1α is essential for the pathogenesis of necrotizing enterocolitis (NEC). HIF-1α is stabilized by glutaredoxin-1 (Grx1) deletion. The precise role of HIF-1α in the intestinal microcirculation in NEC is not well defined. We aimed to determine the role of HIF-1α in the regulation of the intestinal microcirculation during the development of NEC.

METHODS

Experimental NEC was induced in full-term C57BL/6 mice and Grx1 pups through the formula gavage and hypoxia technique. HIF-1α signaling was blocked using the HIF-1α inhibitor, YC-1 [3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole]. Intestinal tissues were collected at predetermined time points for the assessment of the intestinal microcirculation and HIF-1α activity and signaling.

RESULTS

We found that NEC induction impaired the intestinal microcirculation, but the impairment of the intestinal blood flow and capillary density was ameliorated in Grx1 mice. This amelioration was associated with tripeptide glutathione-protein adducts in the intestinal tissue. Grx1 ablation also promoted vascular endothelial growth factor A production in the intestinal tissue. This intestinal microvascular improvement was not found in HIF-1α-inhibited mice, suggesting that HIF-1α was involved in the intestinal microcirculatory perfusion.

CONCLUSIONS

The current data demonstrated that HIF-1α signaling is involved in the intestinal microvascular modification during the pathogenesis of NEC, suggesting that targeting HIF-1α might be a promising strategy for NEC treatment.