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. myometrium | smooth muscle | pH | hypoxia | hypoxic preconditioning P ulsatile releases of oxytocin are important for labor, but as oxytocin knockout mice deliver normally (1), other mechanisms for increasing contractile strength must occur. A puzzling feature of labor is that contractions become progressively stronger as the myometrium (uterine muscle) experiences repetitive metabolic stress from hypoxia. This reaction occurs because as contractions develop they briefly compress the uterine blood vessels (2, 3). Transient decreases of oxygenation, pH, and ATP, all of which if sustained can decrease contractile activity, occur in vivo with each contraction (3-5). Hypoxia regulates a large number of genes, including those governing metabolism and function in many tissues, and changes in genes associated with hypoxia have been identified as key findings in transcriptomic studies of poorly laboring women (6, 7). Chaemsaithong et al. and Mittal et al. confirmed changes in hypoxia-inducible factor 1a (HIF1a) using RT-PCR, as well as overexpression of cyclooxygenase-2 (COX2) in myometrium and endothelial NOS, which is important for blood vessel dilation. There is, however, no empirical evidence showing how such changes could be important to successful labors, and no existing mechanism linking hypoxia to an increase in contractions. In contrast, studies of hypoxia in myometrium and other smooth muscles show it to decrease contractility (8, 9).Of note, however, are studies demonstrating ischemic tolerance as an adaptive response initiated by several exposures to a stressor of mild severity, from which resistance to ischemia is markedly increased. This is known as hypoxic or ischemic preconditioning, and has been best investigated in cardiac muscle (10) and brain (11), where it is considered to be a powerful mechanism for limiting ischemic damage. Given that physiological decreases in oxygenation are part of the normal process of labor (4, 12), this finding therefore raised some important questions: What is the effect of brief but repetitive periods of hypoxia on uterine contractility? And...

Human myometrial artery function and endothelial cell calcium signalling are reduced by obesity: Can this contribute to poor labour outcomes?

“…As noted earlier, during labour there is repetitive compression of the uterine blood vessels and hypoxia and alterations in metabolites . Repetitive transient hypoxia can increase myometrial contractions, HIFI, and may be a mechanism to counter the metabolic changes . Much less well documented, however, is how the vascular myocytes themselves are affected by the compressions, which will increase as labour progresses.…”

The response of rat and human uterus to oxytocin from different gestational stages in vitro

“…Uterine strips were mounted in an organ bath chambers as previously described (Alotaibi et al 2015). Briefly, strips were vertically placed into 5 ml jacketed organ bath chambers (Linton Instruments, UK), filled with buffered PSS solution pre-bubbled with 95% O 2 and 5% CO 2 at 37°C.…”

“…All uterine strips were stretched to a 1 g standard resting tension (Alotaibi et al 2015) and allowed to equilibrate for at least 30 minutes to obtain regular uterine contractions before adding any drug. After obtaining regular spontaneous uterine contractions, OT was added directly to the PSS for 20 minutes and its effect was monitored.…”

“…All stock solutions were made according to the manufacturer's guidelines. The stock solution of OT was made using dH 2 O and a final concentration of OT (5 nM) was used in the study (Alotaibi et al 2015). Nimesulide is a potent selective blocker for PGHS-2 which was dissolved in dimethyl sulfoxide (DMSO), and used at final concentration of 10 μM (Connolly et al 1998).…”

Gestation changes sodium pump isoform expression, leading to changes in ouabain sensitivity, contractility, and intracellular calcium in rat uterus

“…; Alotaibi et al. ). Thus, it is of interest that the β 1 subunit responds to oxidative stress by glutathionylation (Rasmussen et al.…”