Abstract
We have previously proposed that uterine caspase-3 may modulate uterine contractility in a gestationally regulated fashion. The objective of this study was to determine the mechanism by which uterine caspase-3 is activated and consequently controlled in the pregnant uterus across gestation. Utilizing the mouse uterus as our gestational model we examined the intrinsic and extrinsic apoptotic signaling pathways and the endoplasmic reticulum stress response as potential activators of uterine caspase-3 at the transcriptional and translational level. Our study revealed robust activation of the uterine myocyte endoplasmic reticulum stress response and its adaptive unfolded protein response during pregnancy coinciding respectively with increased uterine caspase-3 activity and its withdrawal to term. In contrast the intrinsic and extrinsic apoptotic signaling pathways remained inactive across gestation. We speculate that physiological stimuli experienced by the pregnant uterus likely potentiates the uterine myocyte endoplasmic reticulum stress response resulting in elevated caspase-3 activation, which is isolated to the pregnant mouse myometrium. However as term approaches, activation of an elevated adaptive unfolded protein response acts to limit the endoplasmic reticulum stress response inhibiting caspase-3 resulting in its decline towards term. We speculate that these events have the capacity to regulate gestational length in a caspase-3 dependent manner.
Highlights
Premature labor is the leading cause of neonatal mortality, to date, few effective and broadly applicable interventions are available for the prevention of preterm birth [1]
While we found no evidence of activation of the extrinsic or intrinsic apoptoticsignaling pathways, robust gestationally mediated activation of the endoplasmic reticulum stress response (ERSR) and unfolded protein response (UPR) was observed in the pregnant mouse uterus across gestation
We hypothesize that activation of the ERSR and the resulting UPR in the uterus are central in the non-apoptotic triggering and management of uterine CASP3 activity during pregnancy
Summary
Premature labor is the leading cause of neonatal mortality, to date, few effective and broadly applicable interventions are available for the prevention of preterm birth [1]. In this study we have defined that the uterine myocyte endoplasmic reticulum stress response (ERSR) and its related unfolded protein response (UPR) are the likely regulators of uterine myocyte CASP3 activity during pregnancy. Physiological stimuli such as fluxes in protein synthesis, cellular differentiation, hypoxia and glucose deprivation have been described to result in the accumulation of misfolded proteins and perturbation of ER homeostasis resulting in the activation of the ERSR and its adaptive UPR [5,6,7]. It has been suggested that ER stress induced by oxidative stress in decidual cells may play a role in early pregnancy loss [16,17,18]
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