O-GlcNAc cycling enzymes control vascular development of the placenta by modulating the levels of HIF-1α. Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Yang, Yong Ryoul; Jang, Hyun-Jun; Lee, Yong Hwa; Kim, Il Shin; Lee, Ho; Ryu, Sung Ho; Suh, Pann-Ghill
• Is Part Of: Placenta. Volume 36:Issue 10(2015:Oct.)
• Page Start: 1063
• Page End: 1068
• Publication Date: 2015-10
• Subjects: Placenta -- Periodicals; Reproduction -- Periodicals; Placenta -- Periodicals; Placenta -- Périodiques; Reproduction -- Périodiques; 612.63
• DOI: 10.1016/j.placenta.2015.08.001
• Languages: English
• ISSNs: 0143-4004

Abstract

<abstract xml:lang="en" abstract-type="author" id="abs0010"> <title id="sectitle0010">Abstract</title> <sec> <title id="sectitle0015">Introduction</title> <p id="abspara0010">Placental vasculogenesis is essential for fetal growth and development, and is affected profoundly by oxygen tension (hypoxia). Hypoxia-inducible factor-1α (HIF-1α), which is stabilized at the protein level in response to hypoxia, is essential for vascular morphogenesis in the placenta. Many studies suggested that responses to hypoxia is influenced by O-GlcNAcylation. O-GlcNAcylation is regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) that catalyze the addition and removal of O-GlcNAc respectively.</p> </sec> <sec> <title id="sectitle0020">Methods</title> <p id="abspara0015">We generated OGA deficient mice and evaluated <italic>OGA</italic><sup>−/−</sup> placentas. The analysis of <italic>OGA</italic><sup>−/−</sup> placentas was focused on morphological change and placental vasculogenesis. HIF-1α protein stability or transcriptional activity under dysregulation of O-GlcNAcylation were evaluated by Western blot, RT-qPCR and luciferase reporter gene assays in MEFs or MS1 cell line.</p> </sec> <sec> <title id="sectitle0025">Results</title> <p id="abspara0020">Deletion of OGA results in defective placental vasculogenesis. <italic>OGA</italic><sup>−/−</sup> placentas showed an abnormal placental shape and reduced vasculature in the labyrinth, which caused a developmental delay in the embryos. <italic>OGA</italic> deletion, which elevates O-GlcNAcylation and downregulates O-GlcNAc transferase (OGT), suppressed HIF-1α stabilization and the transcription of its target genes. In contrast, the overexpression of O-GlcNAc cycling enzymes enhanced the expression and transcriptional activity of HIF-1α.</p> </sec> <sec> <title id="sectitle0030">Discussion</title> <p id="abspara0025">These results suggest that OGA plays a critical role in placental vasculogenesis by modulating HIF-1α stabilization. Control of O-GlcNAcylation is essential for placental development.</p> </sec> </abstract>