Skip to main content
SpringerLink
Log in

Endothelin receptor B affects the perfusion of newborn intestine: possible mechanism of necrotizing enterocolitis development

  • Original Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

Abstract

Background

Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases in infancy. Hypoxia is known as one of the major risk factors for the development of NEC. Endothelin, known to regulate vasoconstriction, has two receptors (A and B). However, the role of endothelin receptor B (EDNRB) in neonatal intestinal injury remains unclear. We aimed to investigate whether EDNRB is involved in NEC pathophysiology.

Methods

Following ethical approval (#44032), EDNRB hetero knockout mice pups (EDNRB±) and their wild-type (WT) littermates were studied. NEC was induced from postnatal day 5–9 (P5–P9) by hypoxia, gavage feeding of formula and administration of lipopolysaccharide. On P9, the ileum was harvested.

Results

NEC induction in WT mice was associated with mucosal injury. However, EDNRB± NEC mice had reduced mucosal injury. Similarly, EDNRB± mice had significantly lower expression of IL-6 mRNA compared to WT NEC mice. Pimonidazole immunostaining was also significantly lower in EDNRB± compared to WT NEC, suggesting reduced tissue hypoxia.

Conclusions

Partial knockout of EDNRB results in reduced NEC severity and reduced tissue hypoxia. Intestinal perfusion and hypoxia are important elements of NEC pathogenesis. These findings are relevant to the understanding of NEC pathophysiology and to the development of novel preventive strategies for NEC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Nino DF, Sodhi CP, Hackam DJ (2016) Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol 13:590–600

    Article  CAS  Google Scholar 

  2. Nowicki PT (2005) Ischemia and necrotizing enterocolitis: where, when, and how. Semin Pediatr Surg 14:152–158

    Article  Google Scholar 

  3. Watkins DJ, Besner GE (2013) The role of the intestinal microcirculation in necrotizing enterocolitis. Semin Pediatr Surg 22:83–87

    Article  Google Scholar 

  4. Yanagisawa M, Kurihara H, Kimura S et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415

    Article  CAS  Google Scholar 

  5. Su BY, Reber KM, Nankervis CA (2004) Developmental expression of endothelin receptors in postnatal swine mesenteric artery. Pediatr Res 56:359–365

    Article  CAS  Google Scholar 

  6. Zani A, Cordischi L, Cananzi M et al (2008) Assessment of a neonatal rat model of necrotizing enterocolitis. Eur J Pediatr Surg 18:423–426

    Article  CAS  Google Scholar 

  7. Chen Y, Koike Y, Miyake H et al (2016) Formula feeding and systemic hypoxia synergistically induce intestinal hypoxia in experimental necrotizing enterocolitis. Pediatr Surg Int 32:1115–1119

    Article  CAS  Google Scholar 

  8. Chan KYY, Leung KT, Tam YH et al (2014) Genome-wide expression profiles of necrotizing enterocolitis versus spontaneous intestinal perforation in human intestinal tissues. Ann Surg 260:1128–1137

    Article  Google Scholar 

  9. Ito Y, Doelle SM, Clark JA et al (2007) Intestinal microcirculatory dysfunction during the development of experimental necrotizing enterocolitis. Pediatr Res 61:180–184

    Article  Google Scholar 

  10. Oktar BK, Gulpinar MA, Bozkurt A et al (2002) Endothelin receptor blockers reduce I/R-induced intestinal mucosal injury: role of blood flow. Am J Physiol Gastrointest Liver Physiol 282:G647–G655

    Article  CAS  Google Scholar 

  11. Cuna A, George L, Sampath V (2018) Genetic predisposition to necrotizing enterosolitis in premature infants: Current knowledge, challenges, and future directions. Semin Fetal Neonatal Med 23:387–393

    Article  Google Scholar 

  12. Stobdan T, Zhou D, Ao-leong E et al (2015) Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice. Proc Natl Acad Sci U S A 112:10425–10430

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Dr. Agostino Pierro was supported by the endowment of the Robert M. Filler Chair of Surgery, The Hospital for Sick Children, and by the Canadian Institutes of Health Research (CIHR) Foundation Grant (353857).

Author information

Authors and Affiliations

  1. Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G1X8, Canada

    Hiromu Miyake, Shogo Seo, Carol Lee, Bo Li & Agostino Pierro

  2. Department of Pediatric Surgery, Shizuoka Children’s Hospital, 860 Urushiyama, Aoi-ku, Shizuoka, 4208660, Japan

    Hiromu Miyake

  3. Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Shogo Seo, Naho Fujiwara, Katsumi Miyahara & Atsuyuki Yamataka

  4. Department of Pediatric Surgery, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore

    Yong Chen

Authors
  1. Hiromu Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shogo Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naho Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katsumi Miyahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carol Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Atsuyuki Yamataka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Agostino Pierro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Agostino Pierro.

Ethics declarations

Conflict of interest

The author declares that there is no competing interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyake, H., Seo, S., Fujiwara, N. et al. Endothelin receptor B affects the perfusion of newborn intestine: possible mechanism of necrotizing enterocolitis development. Pediatr Surg Int 35, 1339–1343 (2019). https://doi.org/10.1007/s00383-019-04559-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00383-019-04559-1

Keywords

Search

Navigation