title: Thinking Outside the Box.
abstract: A broad definition of preconditioning is "the preparation for a subsequent action." Mounting evidence demonstrates that novel remote preconditioning paradigms, in which protective stimuli experienced locally can capacitate systemic tolerance and enhanced cell viability upon exposure to ensuing cellular insults, have been largely successful in the field of cardiovascular ischemia/reperfusion injury. To ensure successful protective preconditioning, some models (including the uterus) have been demonstrated to activate the unfolded protein response (UPR), which is a cellular stress response controlled at the level of the endoplasmic reticulum. However, in the context of remote preconditioning, activation of these intracellular molecular pathways must result in the extracellular transmission of adaptive signals to remote targets. In our recently published manuscript, we have described the activation of the UPR in the pregnant uterine myocyte to be associated with increased uterine myocyte quiescence and normal gestational length. We hypothesize that ubiquitous uterine gestational stresses experienced in every pregnancy, which have been demonstrated in other systems to activate the UPR, may induce a robust paracrine dissemination of a uterine secretome, for example, glucose-regulated protein 78, with preconditioning-like properties. Furthermore, we speculate that the gestational stress-induced uterine secretome acts to promote both local and systemic tolerance to the ensuing gestational insults, allowing for the maintenance of uterine quiescence. In this context, preterm labor may be the result of a pregnant uterus experiencing a stress it cannot accommodate or when it is unable to host an appropriate UPR resulting in insufficient preconditioning and a diminished local and systemic capacity to tolerate pregnancy-dependent increases in normal gestational stress. This is highly attractive from a clinical viewpoint as we ultimately aim to identify local and systemic adaptations that may serve as preconditioning stimuli for use as a strategy to restore appropriate preconditioning profiles to prolong uterine quiescence in pregnancy.
authors.affiliation: 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Ingles
authors.affiliation: 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.
authors.forename: Chandrashekara N
authors.initials: CN
authors.lastname: Kyathanahalli
authors.affiliation: 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.|3 Perinatal Research Initiative Wayne State University School of Medicine, Wane State University, Detroit, MI, USA.
authors.forename: Pancharatnam
authors.initials: P
authors.lastname: Jeyasuria
authors.affiliation: 1 Department of Physiology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University Perinatal Initiative, School of Medicine, Wayne State University, Detroit, MI, USA.|3 Perinatal Research Initiative Wayne State University School of Medicine, Wane State University, Detroit, MI, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Condon
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001783:Blood Flow Velocity; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods*; D011247:Pregnancy; D047928:Premature Birth / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D012039:Regional Blood Flow; D015398:Signal Transduction; D056811:Unfolded Protein Response; D014590:Uterine Contraction; D014599:Uterus / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins
keywords: GRP78; preconditioning; preterm labor; secretome; unfolded protein response; uterus