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Fig. 8. Working model of the role of NO and the teratogenic compounds high glucose
and L-NMMA during the development of the yolk sac vasculature in the murine
conceptus. During normal development, stage-specific production of NO by
endodermal iNOS elicits autocrine responses in endodermal cells,
downregulating ROS production and paracrine responses in endothelial cells,
and upregulating eNOS expression. These autocrine and paracrine actions of NO
ultimately facilitate vascular differentiation and development. In the
hyperglycemic condition, endodermal iNOS expression is maintained and the
resultant increased NO generated participates with SO to generate increased
ROS levels, which, in turn, affect the numerous soluble factors required for
mesodermal differentiation and migration. In the presence of L-NMMA,
developmental stage-specific iNOS production of endodermal NO is abrogated,
resulting in the blunting of NO autocrine and paracrine signaling, which, in
turn, affects the myriad of soluble factors required for mesodermal
differentiation and migration. In the presence of a NO donor,
glucose-inhibited yolk sac vascularization proceeds. The exogenous NO
re-establishes the normal timing of the switch in eNOS/iNOS levels and
reconstitutes the NO-driven endodermal and mesodermal signaling pathways,
facilitating normal vascular differentiation and development.
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