Preterm birth remains the most serious complication of pregnancy and is associated with increased rates of infant death or permanent neurodevelopmental disability. Our understanding of the regulation of parturition remains inadequate. The scientific literature, largely derived from rodent animal models, suggests two major mechanisms regulating the timing of parturition: the withdrawal of the steroid hormone progesterone and a proinflammatory response by the immune system. However, available evidence strongly suggests that parturition in the human has significantly different regulators and mediators from those in most of the animal models. Our objectives are to critically review the data and concepts that have arisen from use of animal models for parturition and to rationalize the use of a new model. Many animal models have contributed to advances in our understanding of the regulation of parturition. However, we suggest that those animals dependent on progesterone withdrawal to initiate parturition clearly have a limitation to their translation to the human. In such models, a linear sequence of events (e.g., luteolysis, progesterone withdrawal, uterine activation, parturition) gives rise to the concept of a "trigger" mechanism. Conversely, we propose that human parturition may arise from the concomitant maturation of several systems in parallel. We have termed this novel concept "modular accumulation of physiological systems" (MAPS). We also emphasize the urgency to determine the precise role of the immune system in the process of parturition in situations other than intrauterine infection. Finally, we accentuate the need to develop a nonprimate animal model whose physiology is more relevant to human parturition. We suggest that the guinea pig displays several key physiological characteristics of gestation that more closely resemble human pregnancy than do currently favored animal models. We conclude that the application of novel concepts and new models are required to advance translational research in parturition.
Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: currents (L- and T-type), current, an hyperpolarization-activated current, three voltage-gated currents, two -activated current, -activated current, non-specific cation current, - exchanger, - pump and background current. The magnitudes and kinetics of each current system in a spindle shaped single cell with a specified surface area∶volume ratio is described by differential equations, in terms of maximal conductances, electrochemical gradient, voltage-dependent activation/inactivation gating variables and temporal changes in intracellular computed from known fluxes. These quantifications are validated by the reconstruction of the individual experimental ionic currents obtained under voltage-clamp. Phasic contraction is modeled in relation to the time constant of changing . This integrated model is validated by its reconstruction of the different USMC AP configurations (spikes, plateau and bursts of spikes), the change from bursting to plateau type AP produced by estradiol and of simultaneous experimental recordings of spontaneous AP, and phasic force. In summary, our advanced mathematical model provides a powerful tool to investigate the physiological ionic mechanisms underlying the genesis of uterine electrical E-C coupling of labor and parturition. This will furnish the evolution of descriptive and predictive quantitative models of myometrial electrogenesis at the whole cell and tissue levels.
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
The contribution of Ca2+ released from the sarcoplasmic reticulum (SR) to smooth muscle contractile activation remains poorly understood. By simultaneously monitoring cytosolic [Ca2+] ([Ca2+]i) and force in isolated rat uterine smooth muscle, we report the influence of SR Ca2+ release on contractility during conditions (a) of altered SR Ca2+ homeostasis and (b) where the only source of activating Ca2+ was derived from the SR. In myometria of non‐pregnant rats, ryanodine (1‐50 μM), a modulator of calcium‐induced calcium release (CICR), had no effect on the spontaneous [Ca2+]i or force transients. However, depletion of SR Ca2+ by inhibiting the SR Ca2+‐ATPase (with cyclopiazonic acid (CPA), 20 μM) resulted in an enhancement of spontaneous [Ca2+]i and force transients. In myometria of pregnant rats, although ryanodine had no effect in 40 % of tissues studied it produced a small but significant enhancement of the integrated spontaneous [Ca2+]i and force transient in 60 % of cases. The potentiating effects of CPA were enhanced in myometria of pregnant rats compared with non‐pregnant rats, often resulting in maintained [Ca2+]i increases and contraction. In zero external Ca2+, agonist‐induced SR Ca2+ release resulted in transient increases in [Ca2+]i and force. The magnitude of these agonist‐induced [Ca2+]i and force changes were significantly enhanced in myometria of pregnant rats. No evidence for agonist‐induced Ca2+‐independent force production was observed. These results indicate that CICR plays little role in SR Ca2+ release from the myometrium, and that there are gestational‐dependent alterations in the ability of SR Ca2+ mobilization to contribute to contractile activation. The implications of these findings for the co‐ordination of myometrial [Ca2+]i signalling and contractility are discussed.
A, phasic contractions produced by action potentials following electrical stimulation. B, tonic contraction produced by high K¤ depolarization. The Ca¥ measurements were made from the ratio of the fluorescence signals of indo-1 emitted at 400 and 500 nm. Adapted from Bullock & Wray, 1998. and voltage. The activity and distribution of ion channels depend not just upon the particular smooth muscle preparation, but on developmental and gestational state (Khan, Smith, Morrison & Ashford, 1993;Weir & Archer, 1995;Urena, Franco-Obregon & Lopez-Barneo, 1996). Such differences may well account for much of the diversity found between smooth muscles. Any effect of hypoxia on these channels will affect resting membrane potential and is therefore likely to affect force. A general point to consider is that many ion channels require a basal level of phosphorylation for activation, and hence a fall in [ATP] may reduce current flow (Tewari & Simard, 1994;Hilgemann, 1997), although some Ca¥ channels do not appear to be activated by phosphorylation (Klockner & Isenberg, 1985;Ohya, Kitamura & Kuriyama, 1988; Sperelakis, Xiong, Haddad & Musuda, 1994). The changes in metabolites and ions that occur with hypoxia and which may influence ion channel activity are summarized in Table 1. As will become apparent, in many smooth muscles increased outward K¤ current and decreased inward Ca¥ current can be demonstrated with hypoxia or cyanide, along with increased K¤ efflux and decreased Ca¥ entry.What are the effects of hypoxia on K¤ channels? ATPgated K¤ channels (KATP) are present in smooth muscle and have been proposed as a critical link between cell metabolism and electrical activity, and in particular as forming part of the mechanism underlying the dilatation of coronary and cerebral arterioles during hypoxia (Standen, Quayle, Davies, Brayden, Huang & Nelson, 1989; Daut, Maier-Rudolph, Von Beckerath, Mehrke, Gunther & GoedelMeinen, 1990;Dart & Standen, 1995;Taguchi et al. 1997). Teleologically this makes sense; this channel is inhibited by intracellular ATP (inhibition constant, ké, •10-100 ìÒ). In hypoxia, the fall in [ATP] and increase in [ADP], along with a decrease in intracellular pH (pHé) (see Table 2), will be expected to lead to the opening of the channel and hyperpolarization of the smooth muscle cell. This will result in relaxation of the vessel and increased blood flow to the hypoxic region. Recent work has drawn attention to the gating of similar channels by other nucleotide diphosphates (Zhang & Bolton, 1996), but their role in hypoxia remains to be investigated. So, do KATP channels open in hypoxia? There is good evidence that they do in the vascular studies quoted above. However, the reliance in several studies on glibenclamide to block these channels and show their involvement in the hypoxic process, has been questioned (Zhang & Bolton, 1996). It is also difficult to control for a direct effect of low oxygen on channels. It is also clear that a small membrane depolarization, rather than the predicted hyperpolarizatio...
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In the placental vasculature, where oxygenation may be an important regulator of vascular reactivity, there is a paucity of data on the expression of potassium (K) channels, which are important mediators of vascular smooth muscle tone. We therefore addressed the expression and function of several K channel subtypes in human placentas. The expression of voltage-gated (Kv)2.1, KV9.3, large-conductance Ca2+-activated K channel (BKCa), inward-rectified K+ channel (KIR)6.1, and two-pore domain inwardly rectifying potassium channel-related acid-sensitive K channels (TASK)1 in chorionic plate arteries, veins, and placental homogenate was assessed by RT-PCR and Western blot analysis. Functional activity of K channels was assessed pharmacologically in small chorionic plate arteries and veins by wire myography using 4-aminopyridine, iberiotoxin, pinacidil, and anandamide. Experiments were performed at 20, 7, and 2% oxygen to assess the effect of oxygenation on the efficacy of K channel modulators. KV2.1, KV9.3, BKCa, KIR6.1, and TASK1 channels were all demonstrated to be expressed at the message level. KV2.1, BKCa, KIR6.1, and TASK1 were all demonstrated at the protein level. Pharmacological manipulation of voltage-gated and ATP-sensitive channels produced the most marked modifications in vascular tone, in both arteries and veins. We conclude that K channels play an important role in controlling placental vascular function.
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