The long-range goals of the research are to define the roles of transforming growth factor-beta (TGF-beta) (or similarly acting proteins) in promoting the transition of the uterus from phase 0 to phases 1 and 2 of parturition and that of oxytocin in promoting the transition of the uterus from phase 2 to phase 3. We hypothesize that the modifications in myometrial function that lead to the cellular changes that account for the differences in phenotypes as phase O is suspended and phase 1 of parturition is implemented involve the actions of TGF-beta via multiple mechanisms. TGF-beta acts in myometrium or other cells (i) to oppose selectivity a number of progesterone actions, (ii) to decrease the synthesis of selected heptahelical receptors linked to Galpha/s, (iii) to inhibit adenylyl cyclase activity, (iv) to diminish responsiveness to cAMP, (v) to inhibit the induction of nitric oxide synthase and the activation of soluble guanylyl cyclase, and (vi) to reduce the expression of natriuretic peptide receptors. TGF-beta acts via progesterone receptor independent processes to inhibit the expression of some genes that are induced by progesterone (e.g., enkephalinase) and to stimulate the expression of some genes that are induced by progesterone [e.g., connexin43 (Cx43), parathyroid hormone-related protein (PTH-rP), and endothelin-1 (ET-1)]. We suggest that selective progesterone-opposing actions of TGF-beta, together with the effects of TGF-beta to diminish cAMP and cGMP-mediated processes, should effect the suspension of phase O and, subsequently, the progression from phase 1 to phase 2 of parturition. In addition to defining the actions of TGF-beta, studies are proposed to evaluate the mechanism(s) of latent TGF-beta activation in myometrium via plasmin- and thrombospondin-mediated processes. A host of changes in myometrial properties and gene expression that appear during labor are characteristic of the expected phenotype of phase 3 of parturition. We suggest that oxytocin is the hormone of the puerperium, acting on cells of the myometrium during phase 1 and 2 of parturition to facilitate the development of the functional phenotype of uterine phase 3. Studies are described to define the role of oxytocin in the induction of genes that encode proteins essential for the puerperal involution of the uterus, i.e., leukocyte chemoattractants and interstitial collagenase. The studies proposed complement those designed to characterize the functional phenotypes of the uterus during pregnancy (before and during labor) and to evaluate the cellular changes that account for the phenotypic differences.
| Mahendroo, Mala (2018) Cervical hyaluronan biology in pregnancy, parturition and preterm birth. Matrix Biol : |
| Mendelson, Carole R; Montalbano, Alina P; Gao, Lu (2017) Fetal-to-maternal signaling in the timing of birth. J Steroid Biochem Mol Biol 170:19-27 |
| Chen, Chien-Cheng; Montalbano, Alina P; Hussain, Imran et al. (2017) The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression. J Biol Chem 292:12560-12576 |
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| Eskiocak, Ugur; Ramesh, Vijayashree; Gill, Jennifer G et al. (2016) Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma. Nat Commun 7:12336 |
| Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C et al. (2015) Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J Clin Invest 125:2808-24 |
| Renthal, Nora E; Williams, Koriand'r C; Montalbano, Alina P et al. (2015) Molecular Regulation of Parturition: A Myometrial Perspective. Cold Spring Harb Perspect Med 5: |
| Mogami, Haruta; Keller, Patrick W; Shi, Haolin et al. (2014) Effect of thrombin on human amnion mesenchymal cells, mouse fetal membranes, and preterm birth. J Biol Chem 289:13295-307 |
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