title: Hypoxia-induced force increase (HIFI) is a novel mechanism underlying the strengthening of labor contractions, produced by hypoxic stresses.
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.
authors.affiliation: 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.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alotaibi
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Arrowsmith
authors.affiliation: 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 s.wray@liv.ac.uk.
authors.forename: Susan
authors.initials: S
authors.lastname: Wray
mesh_terms: D000143:Acids / Q000378:metabolism; D000222:Adaptation, Physiological / Q000187:drug effects; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D007743:Labor, Obstetric / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects / Q000503:physiopathology; D010100:Oxygen / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D011247:Pregnancy; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000143:Acids; D043682:Receptor, Adenosine A1; D058486:Receptors, Purinergic P2X7; D010121:Oxytocin; D000255:Adenosine Triphosphate; D051546:Cyclooxygenase 2; D000241:Adenosine; D010100:Oxygen; D002118:Calcium
keywords: hypoxia; hypoxic preconditioning; myometrium; pH; smooth muscle