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Hypoxia-induced force increase (HIFI) is a novel mechanism underlying the strengthening of labor contractions, produced by hypoxic stresses

  1. Susan Wray2
  1. Department of Cellular and Molecular Physiology, Harris/Wellbeing Centre for Preterm Birth Research, Institute of Translational Medicine, University of Liverpool, Liverpool L8 7SS, United Kingdom

  1. Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved June 23, 2015 (received for review February 19, 2015)

Significance

Parturition requires strong uterine contractions. A longstanding enigma has been how contractions strengthen despite also causing transient ischemia as they occlude uterine blood vessels. Here we demonstrate a hitherto undescribed mechanism whereby in an adaptation at labor, brief hypoxia in uterine muscle, stimulates the contractile activity. We have named this hypoxia-induced force increase, or HIFI. We identify the underlying mechanism, which involves adenosine and prostaglandin and a rise in intracellular calcium, and show it is present in animal and human uterus, but only close to delivery. We speculate that aberrations in this powerful mechanism could underlie contractions being triggered too early (preterm labor) or if HIFI is deficient, weak contractions, and thus poor and unsuccessful term labors.

Abstract

For successful birth, contractions need to become progressively stronger. The underlying mechanisms are unknown, however. We have found that a novel mechanism, hypoxia-induced force increase (HIFI), is switched on selectively, at term, and is essential to strengthening contractions. HIFI is initiated as contractions cyclically reduce blood flow and produce repeated hypoxic stresses, with associated metabolic and transcriptomic changes. The increases in contractility are a long-lasting, oxytocin-independent, intrinsic mechanism present only in the full-term pregnant uterus. HIFI is inhibited by adenosine receptor antagonism and blockade of cyclooxygenase-2 signaling, and partially reproduced by brief episodes of acidic (but not alkalotic) pH. HIFI explains how labor can progress despite paradoxical metabolic challenge, and provides a new mechanistic target for the 1 in 10 women suffering dysfunctional labor because of poor contractions.

Footnotes

  • ↵1Present address: Department of Physiology, College of Medicine, King Saud University, Riyadh 11461, Kingdom of Saudi Arabia.

  • ↵2To whom correspondence should be addressed. Email: s.wray{at}liv.ac.uk.

  • Author contributions: M.A., S.A., and S.W. designed research; M.A. and S.A. performed research; M.A. and S.W. analyzed data; and M.A. and S.W. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1503497112/-/DCSupplemental.

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