Potassium channel functions in human placental syncytiotrophoblast

The functions of the human placenta depend on the syncytiotrophoblast (STB), a highly specialised multinucleated epithelium. STB transfers nutrients to the fetus and secretes hormones that are required to support fetal development. Throughout normal pregnancy STB is renewed by cell turnover which in...

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Autor: Díaz Rodríguez, Paula Carolina
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2013
País:Chile
OAI Identifier:oai:repositorio.anid.cl:10533/236618
Acceso en línea:https://hdl.handle.net/10533/236618
Access Level:acceso abierto
Palabra clave:Medicina y Ciencias de la Salud
Medicina Básica
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dc.title.es_CL.fl_str_mv Potassium channel functions in human placental syncytiotrophoblast
title Potassium channel functions in human placental syncytiotrophoblast
spellingShingle Potassium channel functions in human placental syncytiotrophoblast
Díaz Rodríguez, Paula Carolina
Medicina y Ciencias de la Salud
Medicina Básica
title_short Potassium channel functions in human placental syncytiotrophoblast
title_full Potassium channel functions in human placental syncytiotrophoblast
title_fullStr Potassium channel functions in human placental syncytiotrophoblast
title_full_unstemmed Potassium channel functions in human placental syncytiotrophoblast
title_sort Potassium channel functions in human placental syncytiotrophoblast
dc.creator.none.fl_str_mv Díaz Rodríguez, Paula Carolina
author Díaz Rodríguez, Paula Carolina
author_facet Díaz Rodríguez, Paula Carolina
author_role author
dc.contributor.advisor.none.fl_str_mv Greenwood, Susan L.
Sibley, Colin P.
dc.contributor.institution.es_CL.fl_str_mv UNIVERSITY OF MANCHESTER
dc.subject.oecd1n.es_CL.fl_str_mv Medicina y Ciencias de la Salud
topic Medicina y Ciencias de la Salud
Medicina Básica
dc.subject.oecd2n.es_CL.fl_str_mv Medicina Básica
description The functions of the human placenta depend on the syncytiotrophoblast (STB), a highly specialised multinucleated epithelium. STB transfers nutrients to the fetus and secretes hormones that are required to support fetal development. Throughout normal pregnancy STB is renewed by cell turnover which involves proliferation, migration and fusion/differentiation of cytotrophoblasts, balanced by apoptosis/autophagy. Dysregulation of STB renewal underlies pre-eclampsia (PE), a serious pregnancy disease, but the mechanisms remain to be elucidated. Potassium (K+) channels facilitate fusion and differentiation, cellular events critical for tissue renewal. K+ channels are regulated by partial pressure of oxygen (pO2), reactive oxygen (ROS) and nitrogen (RNS) species. K+ channel function could be modulated in PE which is characterised by altered placental pO2 and increased oxidative and nitrative stress. This thesis tested the hypotheses that K+ channels participate in STB renewal and human chorionic gonadotropin (hCG) secretion and that dysregulation of K+ channel function, by pO2 and/or elevated ROS/RNS, could contribute to the abnormal STB turnover and endocrine secretion that is a feature of PE. Three aims were pursued: 1) To determine whether pO2 and ROS modulate STB hCG secretion through an effect on K+ channels. Placental villous tissue was cultured in 1%, 6% and 21% pO2 and K+ channel activity (86-rubidium (86Rb) efflux) and hCG secretion were determined. STB voltage-gated K+ channel (KV) activity and hCG secretion was greater in 21% than 6% pO2 and KV blockers reduced hCG secretion at 21% but not 6% pO2. ROS had pO2-dependent effects on both hCG secretion and STB K+ channel activity but causal links between the two remain to be established. Altered pO2 and elevated ROS in PE could modulate KV channel activity leading to altered STB hCG secretion and compromised STB renewal; 2) To determine whether intermediate conductance calcium-activated K+ channels (IKCa) participate in cytotrophoblast morphological and/or biochemical differentiation. Cytotrophoblasts were isolated from normal term placentas and studied at 15/42h (mononucleate) and 66h (multinucleate) of culture. Cytotrophoblasts expressed IKCa protein, and IKCa was activated by the opener DCEBIO, or hyposmotic cell swelling, but was normally quiescent. Chronic activation of IKCa by DCEBIO inhibited cytotrophoblast multinucleation and hCG secretion, an effect which may be mediated by altered cytotrophoblast volume homeostasis. Inappropriate activation of IKCa could compromise STB turnover and volume homeostasis in PE; 3) Having demonstrated that pharmacological activation of IKCa inhibits cytotrophoblast differentiation in vitro, the aim was to determine whether IKCa is activated by nitrative stress. Acute exposure to nitrative stress reversibly activated TRAM-34 (IKCa blocker)-sensitive 86Rb efflux from cytotrophoblasts. Chronic nitrative stress inhibited cytotrophoblast hCG secretion but whether this reduction is through an effect on IKCa remains to be confirmed. This suggests that under conditions of increased nitrative stress in PE, IKCa could be activated contributing to dysregulated STB renewal. Overall the results confirm the hypotheses that K+ channels participate in processes of STB renewal and that their dysregulation by altered pO2 and/or ROS/RNS could contribute to abnormal STB renewal in PE. K+ channels play a fundamental role in regulating a wide range of cellular functions and knowledge of K+ channels and their regulation in STB is fundamental to understand placental physiology and pathophysiology.
publishDate 2013
dc.date.issued.es_CL.fl_str_mv 2013
dc.date.accessioned.none.fl_str_mv 2019-11-18T12:52:52Z
2022-08-18T17:46:39Z
dc.date.available.none.fl_str_mv 2019-11-18T12:52:52Z
2022-08-18T17:46:39Z
dc.type.none.fl_str_mv Tesis Doctorado
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spelling UNIVERSITY OF MANCHESTERDíaz Rodríguez, Paula Carolina2013https://hdl.handle.net/10533/236618http://purl.org/coar/access_right/c_abf2Medicina BásicaMedicina y Ciencias de la SaludPotassium channel functions in human placental syncytiotrophoblastGreenwood, Susan L.Sibley, Colin P.UNIVERSITY OF MANCHESTERReino UnidoDíaz Rodríguez, Paula Carolina2019-11-18T12:52:52Z2022-08-18T17:46:39Z2019-11-18T12:52:52Z2022-08-18T17:46:39Z2013The functions of the human placenta depend on the syncytiotrophoblast (STB), a highly specialised multinucleated epithelium. STB transfers nutrients to the fetus and secretes hormones that are required to support fetal development. Throughout normal pregnancy STB is renewed by cell turnover which involves proliferation, migration and fusion/differentiation of cytotrophoblasts, balanced by apoptosis/autophagy. Dysregulation of STB renewal underlies pre-eclampsia (PE), a serious pregnancy disease, but the mechanisms remain to be elucidated. Potassium (K+) channels facilitate fusion and differentiation, cellular events critical for tissue renewal. K+ channels are regulated by partial pressure of oxygen (pO2), reactive oxygen (ROS) and nitrogen (RNS) species. K+ channel function could be modulated in PE which is characterised by altered placental pO2 and increased oxidative and nitrative stress. This thesis tested the hypotheses that K+ channels participate in STB renewal and human chorionic gonadotropin (hCG) secretion and that dysregulation of K+ channel function, by pO2 and/or elevated ROS/RNS, could contribute to the abnormal STB turnover and endocrine secretion that is a feature of PE. Three aims were pursued: 1) To determine whether pO2 and ROS modulate STB hCG secretion through an effect on K+ channels. Placental villous tissue was cultured in 1%, 6% and 21% pO2 and K+ channel activity (86-rubidium (86Rb) efflux) and hCG secretion were determined. STB voltage-gated K+ channel (KV) activity and hCG secretion was greater in 21% than 6% pO2 and KV blockers reduced hCG secretion at 21% but not 6% pO2. ROS had pO2-dependent effects on both hCG secretion and STB K+ channel activity but causal links between the two remain to be established. Altered pO2 and elevated ROS in PE could modulate KV channel activity leading to altered STB hCG secretion and compromised STB renewal; 2) To determine whether intermediate conductance calcium-activated K+ channels (IKCa) participate in cytotrophoblast morphological and/or biochemical differentiation. Cytotrophoblasts were isolated from normal term placentas and studied at 15/42h (mononucleate) and 66h (multinucleate) of culture. Cytotrophoblasts expressed IKCa protein, and IKCa was activated by the opener DCEBIO, or hyposmotic cell swelling, but was normally quiescent. Chronic activation of IKCa by DCEBIO inhibited cytotrophoblast multinucleation and hCG secretion, an effect which may be mediated by altered cytotrophoblast volume homeostasis. Inappropriate activation of IKCa could compromise STB turnover and volume homeostasis in PE; 3) Having demonstrated that pharmacological activation of IKCa inhibits cytotrophoblast differentiation in vitro, the aim was to determine whether IKCa is activated by nitrative stress. Acute exposure to nitrative stress reversibly activated TRAM-34 (IKCa blocker)-sensitive 86Rb efflux from cytotrophoblasts. Chronic nitrative stress inhibited cytotrophoblast hCG secretion but whether this reduction is through an effect on IKCa remains to be confirmed. This suggests that under conditions of increased nitrative stress in PE, IKCa could be activated contributing to dysregulated STB renewal. Overall the results confirm the hypotheses that K+ channels participate in processes of STB renewal and that their dysregulation by altered pO2 and/or ROS/RNS could contribute to abnormal STB renewal in PE. 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