O-GlcNAc cycling enzymes control vascular development of the placenta by modulating the levels of HIF-1α.
BACKGROUND
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.


METHODS
We generated OGA deficient mice and evaluated OGA(-/-) placentas. The analysis of OGA(-/-) 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.


RESULTS
Deletion of OGA results in defective placental vasculogenesis. OGA(-/-) placentas showed an abnormal placental shape and reduced vasculature in the labyrinth, which caused a developmental delay in the embryos. OGA 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.


CONCLUSIONS
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.
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Yong Ryoul
YR
Yang
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea; Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
Hyun-Jun
HJ
Jang
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Yong Hwa
YH
Lee
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Il Shin
IS
Kim
Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Ho
H
Lee
Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
Sung Ho
SH
Ryu
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. Electronic address: pgsuh@unist.ac.kr.
Pann-Ghill
PG
Suh
D000818:Animals; D002460:Cell Line; D005260:Female; D000860:Hypoxia / Q000201:enzymology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010920:Placenta / Q000098:blood supply* / Q000196:embryology / Q000201:enzymology; D021041:Placental Circulation; D011247:Pregnancy; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases
HIF-1α; Hypoxia; O-GlcNAcylation; OGA; OGT; Placenta; Vasculogenesis