The endothelin-converting enzyme-1/endothelin-1 pathway plays a critical role in inflammation-associated premature delivery in a mouse model

Am J Pathol. 2008 Oct;173(4):1077-84. doi: 10.2353/ajpath.2008.080257. Epub 2008 Sep 4.

Abstract

Premature delivery occurs in 12% of all births and accounts for nearly half of long-term morbidity. Current therapeutic approaches to preterm delivery are ineffective and present serious risks to both mother and fetus. The single most common cause of preterm birth is infection. Previous in vitro investigations have shown that endothelin-1 (ET-1) is induced by inflammatory cytokines and that it increases myometrial smooth muscle tone. Furthermore, we have previously shown that both the endothelin-converting enzyme-1 (ECE-1) inhibitor, phosphoramidon, as well as a novel ET-1 receptor A antagonist synthesized by our group, control premature delivery in a mouse model of inflammation-associated preterm delivery. In the current work, we show that levels of both ET-1 and ECE-1 are increased in gestational tissues in E16.5 mice induced to deliver prematurely after lipopolysaccharide administration. We also show that premature delivery is controlled by treatment with the selective endothelin receptor A antagonist BQ-123 in a dose-dependent manner. Finally, we show here for the first time that premature delivery can be controlled using RNA silencing, by hydrodynamic transfection of E15 mice with ECE-1 RNAi. Taken together, these data support a critical role for the ECE-1/ET-1 system in inflammation-associated premature delivery. The ability to control premature delivery by antagonizing or silencing the ECE-1/ET-1 system offers a novel approach to an unmet clinical need.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aspartic Acid Endopeptidases / metabolism*
  • Endothelin A Receptor Antagonists
  • Endothelin-1 / metabolism*
  • Endothelin-Converting Enzymes
  • Female
  • Immunohistochemistry
  • Inflammation / enzymology*
  • Lipopolysaccharides / pharmacology
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal*
  • Obstetric Labor, Premature / enzymology
  • Peptides, Cyclic / pharmacology
  • Placenta / cytology
  • Placenta / drug effects
  • Placenta / enzymology
  • Pregnancy
  • Premature Birth / enzymology*
  • RNA, Small Interfering / metabolism
  • Uterus / cytology
  • Uterus / drug effects
  • Uterus / enzymology

Substances

  • Endothelin A Receptor Antagonists
  • Endothelin-1
  • Lipopolysaccharides
  • Peptides, Cyclic
  • RNA, Small Interfering
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • Ece1 protein, mouse
  • Endothelin-Converting Enzymes
  • cyclo(Trp-Asp-Pro-Val-Leu)