title: Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP-PKA Signaling Pathway.
abstract: The effects of fluid shear stress (FSS) on the human syncytiotrophoblast and its biological functions have never been studied. During pregnancy, the syncytiotrophoblast is the main source of placental growth factor (PlGF), a proangiogenic factor involved in the placental angiogenesis and the vascular adaptation to pregnancy. The role of FSS in regulating PlGF expression in syncytiotrophoblasts is unknown. We investigated the impact of FSS on the production and secretion of the PlGF by the human syncytiotrophoblasts in primary cell culture. Laminar and continuous FSS (1 dyn cm-2) was applied to human syncytiotrophoblasts cultured in a parallel-plate flow chambers. Secreted levels of PlGF, sFlt-1 (soluble fms-like tyrosin kinase-1), and prostaglandin E2 were tested by immunologic assay. PlGF levels of mRNA and intracellular protein were examined by RT-PCR and Western blot, respectively. Intracellular cAMP levels were examined by time-resolved fluorescence resonance energy transfer cAMP accumulation assay. Production of cAMP and PlGF secretion was significantly increased in FSS conditions compared with static conditions. Western blot analysis of cell extracts exposed to FSS showed an increased phosphorylation of protein kinase A substrates and cAMP response element-binding protein on serine 133. FSS-induced phosphorylation of cAMP response element-binding protein and upregulation of PlGF were prevented by inhibition of protein kinase A with H89 (3 μmol/L). FSS also triggers intracellular calcium flux, which increases the synthesis and release of prostaglandin E2. The enhanced intracellular cAMP in FSS conditions was blocked by COX1/COX2 (cyclooxygenase) inhibitors, suggesting that the increase in prostaglandin E2 production could activate the cAMP/protein kinase A pathway in an autocrine/paracrine fashion. FSS activates the cAMP/protein kinase A pathway leading to upregulation of PlGF in human syncytiotrophoblast.
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.). edouard.lecarpentier@wanadoo.fr.
authors.forename: Edouard
authors.initials: E
authors.lastname: Lecarpentier
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Anthony
authors.initials: A
authors.lastname: Atallah
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Jean
authors.initials: J
authors.lastname: Guibourdenche
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Marylise
authors.initials: M
authors.lastname: Hebert-Schuster
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Sarah
authors.initials: S
authors.lastname: Vieillefosse
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Audrey
authors.initials: A
authors.lastname: Chissey
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Bassam
authors.initials: B
authors.lastname: Haddad
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pidoux
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Daniele
authors.initials: D
authors.lastname: Evain-Brion
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Abdul
authors.initials: A
authors.lastname: Barakat
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Thierry
authors.initials: T
authors.lastname: Fournier
authors.affiliation: From the INSERM, UMR-S 1139, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., B.H., G.P., T.F., V.T.); PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France (E.L., A.A., J.G., M.H.-S., S.V., A.C., T.F., V.T.); Port Royal Maternity, Department of Gynecology Obstetrics I, Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (E.L., V.T.); DHU Risques et grossesse, Paris, France (E.L., J.G., T.F., V.T.); PremUP Foundation, Paris, France (E.L., J.G., D.E.-B., T.F., V.T.); Laboratoire d'Hydrodynamique (LadHyX), CNRS, École Polytechnique, Palaiseau, France (A.B.); SDBA Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (M.H.-S.); Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, CRC CHI Creteil, University Paris Est Creteil, France (B.H.); Service d'hormonologie Centre Hospitalier Universitaire Cochin Broca Hôtel Dieu, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpital de Paris, France (J.G.); and INSERM, UMR-S 1180, Université Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France (G.P.).
authors.forename: Vassilis
authors.initials: V
authors.lastname: Tsatsaris
mesh_terms: D000704:Analysis of Variance; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics*; D010920:Placenta / Q000378:metabolism / Q000503:physiopathology; D000072483:Placenta Growth Factor / Q000235:genetics*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000235:genetics; D013314:Stress, Mechanical; D014327:Trophoblasts / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; C098069:PIGF protein, human; D012333:RNA, Messenger; D000072483:Placenta Growth Factor
keywords: calcium signaling; cell extracts; phosphorylation; placental growth factor; trophoblast