Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta
Identifieur interne : 003638 ( Main/Exploration ); précédent : 003637; suivant : 003639Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta
Auteurs : Manyu Li [États-Unis] ; Nicole M. J. Schwerbrock [États-Unis] ; Patricia M. Lenhart [États-Unis] ; Kimberly L. Fritz-Six [États-Unis] ; Mahita Kadmiel [États-Unis] ; Kathleen S. Christine [États-Unis] ; Daniel M. Kraus [États-Unis] ; Scott T. Espenschied [États-Unis] ; Helen H. Willcockson [États-Unis] ; Christopher P. Mack [États-Unis] ; Kathleen M. Caron [États-Unis]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2013.
Abstract
The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.
Url:
DOI: 10.1172/JCI67039
PubMed: 23635772
PubMed Central: 3668816
Affiliations:
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placenta</title><author><name sortKey="Li, Manyu" sort="Li, Manyu" uniqKey="Li M" first="Manyu" last="Li">Manyu Li</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Schwerbrock, Nicole M J" sort="Schwerbrock, Nicole M J" uniqKey="Schwerbrock N" first="Nicole M. J." last="Schwerbrock">Nicole M. J. Schwerbrock</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Lenhart, Patricia M" sort="Lenhart, Patricia M" uniqKey="Lenhart P" first="Patricia M." last="Lenhart">Patricia M. Lenhart</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Fritz Six, Kimberly L" sort="Fritz Six, Kimberly L" uniqKey="Fritz Six K" first="Kimberly L." last="Fritz-Six">Kimberly L. Fritz-Six</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Kadmiel, Mahita" sort="Kadmiel, Mahita" uniqKey="Kadmiel M" first="Mahita" last="Kadmiel">Mahita Kadmiel</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Christine, Kathleen S" sort="Christine, Kathleen S" uniqKey="Christine K" first="Kathleen S." last="Christine">Kathleen S. Christine</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Kraus, Daniel M" sort="Kraus, Daniel M" uniqKey="Kraus D" first="Daniel M." last="Kraus">Daniel M. Kraus</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Espenschied, Scott T" sort="Espenschied, Scott T" uniqKey="Espenschied S" first="Scott T." last="Espenschied">Scott T. Espenschied</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Willcockson, Helen H" sort="Willcockson, Helen H" uniqKey="Willcockson H" first="Helen H." last="Willcockson">Helen H. Willcockson</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Mack, Christopher P" sort="Mack, Christopher P" uniqKey="Mack C" first="Christopher P." last="Mack">Christopher P. Mack</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Caron, Kathleen M" sort="Caron, Kathleen M" uniqKey="Caron K" first="Kathleen M." last="Caron">Kathleen M. Caron</name><affiliation wicri:level="2"><nlm:aff id="JCI67039">Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The remodeling of maternal uterine spiral arteries (SAs) is an essential process for
ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of
SAs to remodel is causally associated with preeclampsia, a common and
life-threatening complication of pregnancy that is harmful to both mother and fetus.
Here, using both loss-of-function and gain-of-function genetic mouse models, we show
that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal
trophoblast cells is necessary and sufficient to promote appropriate recruitment and
activation of maternal uterine NK (uNK) cells to the placenta and ultimately
facilitate remodeling of maternal SAs. Placentas that lacked either AM or its
receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA
remodeling and reendothelialization, and markedly reduced numbers of maternal uNK
cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a
concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently
stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells,
which in turn induced VSMC apoptosis. These data identify an essential function for
fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore
the importance of exploring AM as a biomarker and therapeutic agent for
preeclampsia.</p></div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li></region></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Li, Manyu" sort="Li, Manyu" uniqKey="Li M" first="Manyu" last="Li">Manyu Li</name></region><name sortKey="Caron, Kathleen M" sort="Caron, Kathleen M" uniqKey="Caron K" first="Kathleen M." last="Caron">Kathleen M. Caron</name><name sortKey="Christine, Kathleen S" sort="Christine, Kathleen S" uniqKey="Christine K" first="Kathleen S." last="Christine">Kathleen S. Christine</name><name sortKey="Espenschied, Scott T" sort="Espenschied, Scott T" uniqKey="Espenschied S" first="Scott T." last="Espenschied">Scott T. Espenschied</name><name sortKey="Fritz Six, Kimberly L" sort="Fritz Six, Kimberly L" uniqKey="Fritz Six K" first="Kimberly L." last="Fritz-Six">Kimberly L. Fritz-Six</name><name sortKey="Kadmiel, Mahita" sort="Kadmiel, Mahita" uniqKey="Kadmiel M" first="Mahita" last="Kadmiel">Mahita Kadmiel</name><name sortKey="Kraus, Daniel M" sort="Kraus, Daniel M" uniqKey="Kraus D" first="Daniel M." last="Kraus">Daniel M. Kraus</name><name sortKey="Lenhart, Patricia M" sort="Lenhart, Patricia M" uniqKey="Lenhart P" first="Patricia M." last="Lenhart">Patricia M. Lenhart</name><name sortKey="Mack, Christopher P" sort="Mack, Christopher P" uniqKey="Mack C" first="Christopher P." last="Mack">Christopher P. Mack</name><name sortKey="Schwerbrock, Nicole M J" sort="Schwerbrock, Nicole M J" uniqKey="Schwerbrock N" first="Nicole M. J." last="Schwerbrock">Nicole M. J. Schwerbrock</name><name sortKey="Willcockson, Helen H" sort="Willcockson, Helen H" uniqKey="Willcockson H" first="Helen H." last="Willcockson">Helen H. Willcockson</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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