title: A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia.
abstract: Placental trophoblasts (TBs) invade and remodel uterine vessels with an arterial bias. This process, which involves vascular mimicry, re-routes maternal blood to the placenta, but fails in pre-eclampsia. We investigated Notch family members in both contexts, as they play important roles in arterial differentiation/function. Immunoanalyses of tissue sections showed step-wise modulation of Notch receptors/ligands during human TB invasion. Inhibition of Notch signaling reduced invasion of cultured human TBs and expression of the arterial marker EFNB2. In mouse placentas, Notch activity was highest in endovascular TBs. Conditional deletion of Notch2, the only receptor upregulated during mouse TB invasion, reduced arterial invasion, the size of maternal blood canals by 30-40% and placental perfusion by 23%. By E11.5, there was litter-wide lethality in proportion to the number of mutant offspring. In pre-eclampsia, expression of the Notch ligand JAG1 was absent in perivascular and endovascular TBs. We conclude that Notch signaling is crucial for TB vascular invasion.
authors.affiliation: Center for Reproductive Sciences, University of California-San Francisco, CA 94143, USA.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Hunkapiller
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Gasperowicz
authors.forename: Mirhan
authors.initials: M
authors.lastname: Kapidzic
authors.forename: Vicki
authors.initials: V
authors.lastname: Plaks
authors.forename: Emin
authors.initials: E
authors.lastname: Maltepe
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.forename: Jay C
authors.initials: JC
authors.lastname: Cross
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001158:Arteries / Q000254:growth & development; D002135:Calcium-Binding Proteins / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D036388:Ephrin-B2 / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D021041:Placental Circulation / Q000502:physiology*; D011225:Pre-Eclampsia / Q000503:physiopathology*; D011247:Pregnancy; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D014327:Trophoblasts / Q000378:metabolism / Q000502:physiology*; D014599:Uterus / Q000098:blood supply*
chemical_list: D002135:Calcium-Binding Proteins; D017931:DNA Primers; D036388:Ephrin-B2; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins