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dc.contributor.authorCao, Songying
dc.contributor.authorReece, E Albert
dc.contributor.authorShen, Wei-Bin
dc.contributor.authorYang, Peixin
dc.date.accessioned2020-10-30T16:00:44Z
dc.date.available2020-10-30T16:00:44Z
dc.date.issued2020-10-15
dc.identifier.urihttp://hdl.handle.net/10713/13990
dc.description.abstractDuring mouse embryonic development, vasculogenesis initially occurs in the yolk sac, preceding neurulation. Our previous studies have demonstrated that maternal diabetes induces embryonic vasculopathy at early embryonic developmental stage by suppressing the expression of vascular growth factors including BMP4 (bone morphogenetic protein 4). This study aimed to determine whether restoring diabetes-inhibited BMP4 expression in Flk-1+ progenitors effectively prevented maternal diabetes-induced embryonic vasculopathy and NTDs. Transgenic (Tg) BMP4 expression in the vascular endothelial growth factor receptor 2 (Flk-1)-positive (Flk-1+) progenitors was achieved by crossing a Floxed BMP4 Tg mouse line with the Flk-1-Cre mouse line. Non-BMP4 Tg and BMP4 Tg embryos were harvested at E8.5 to assess the expression of BMP4, markers of endoplasmic reticulum stress, and expression of the Id genes, direct targets of BMP4; and the presence of cleaved caspase 3 and 8, apoptosis, and Smad signaling. BMP4 Tg overexpression neutralized its down-regulation by maternal diabetes in E8.5 embryos. Maternal diabetes-induced Flk-1+ progenitor apoptosis, impairment of blood island formation, and reduction of Flk-1+ progenitor number and blood vessel density, which were reversed by BMP4 Tg expression. BMP4 Tg expression in Flk-1+ progenitors blocked maternal diabetes-induced vasculopathy in early stage embryos (E7.5-E8.5) and consequently led to amelioration of maternal diabetes-induced neural tube defects (NTDs) at E10.5. BMP4 Tg expression inhibited maternal diabetes-induced endoplasmic reticulum stress and caspase cascade activation in the developing neuroepithelium, and reduced neuroepithelial cell apoptosis. BMP4 Tg expression re-activated Smad1/5/8 phosphorylation and reversed maternal diabetes-suppressed Smad4 expression. BMP4 Tg expression restored Id1 and Smad6 expression inhibited by maternal diabetes. In vitro, recombinant BMP4 protein blocked high glucose-induced Flk-1+ progenitor apoptosis and NTDs. These data demonstrate that BMP4 down-regulation in Flk-1+ progenitors are responsible for diabetes-induced yolk sac vasculopathy, and that restoring BMP4 expression prevents vasculopathy and rescues neuroepithelial cells from cellular organelle stress, leading to NTD reduction.en_US
dc.description.urihttps://doi.org/10.1038/s41419-020-03078-5en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofCell Death & Diseaseen_US
dc.subject.meshBone Morphogenetic Protein 4en_US
dc.subject.meshMiceen_US
dc.subject.meshGestational Ageen_US
dc.subject.meshPregnancyen_US
dc.subject.meshFemaleen_US
dc.subject.meshDiabetes, Gestationalen_US
dc.subject.meshVascular Endothelial Growth Factor Aen_US
dc.subject.meshApoptosisen_US
dc.subject.meshNeural Tube Defectsen_US
dc.titleRestoring BMP4 expression in vascular endothelial progenitors ameliorates maternal diabetes-induced apoptosis and neural tube defects.en_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41419-020-03078-5
dc.identifier.pmid33060561
dc.source.journaltitleCell death & disease
dc.source.volume11
dc.source.issue10
dc.source.beginpage859
dc.source.endpage
dc.source.countryEngland


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