title: Focal adhesion signaling is required for myometrial ERK activation and contractile phenotype switch before labor.
abstract: In late pregnancy rapidly increasing fetal growth dramatically increases uterine wall tension. This process has been implicated in the activation of the myometrium for labor, but the mechanisms involved are unclear. Here, we tested, using a rat model, the hypothesis that gestation-dependent stretch, via activation of focal adhesion signaling, contributes to the published activation of myometrial ERK at the end of pregnancy. Consistent with this hypothesis, we show here that ERK is targeted to adhesion plaques during late pregnancy. Furthermore, myometrial stretch triggers a dramatic increase in myometrial contractility and ERK and caldesmon phosphorylation, confirming the presence of stretch sensitive myometrial signaling element. Screening by anti-phosphotyrosine immunoblotting for focal adhesion signaling in response to stretch reveals a significant increase in the tyrosine phosphorylated bands identified as focal adhesion kinase (FAK), A-Raf, paxillin, and Src. Pretreatment with PP2, a Src inhibitor, significantly suppresses the stretch-induced increases in FAK, paxillin, Src, ERK and caldesmon phosphorylation and myometrial contractility. Thus, focal adhesion-Src signaling contributes to ERK activation and promotes contraction in late pregnancy. These results point to focal adhesion signaling molecules as potential targets in the modulation of the myometrial contractility and the onset of labor.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. yli1@bidmc.harvard.edu
authors.forename: Yunping
authors.initials: Y
authors.lastname: Li
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gallant
authors.forename: Sabah
authors.initials: S
authors.lastname: Malek
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Morgan
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000502:physiology*; D066298:In Vitro Techniques; D009215:Myometrium / Q000201:enzymology / Q000502:physiology*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D048491:Proto-Oncogene Proteins A-raf / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D014590:Uterine Contraction; D014599:Uterus / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C412373:AG 1879; D002148:Calmodulin-Binding Proteins; D051419:Paxillin; D011743:Pyrimidines; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D048491:Proto-Oncogene Proteins A-raf; D048049:Extracellular Signal-Regulated MAP Kinases