PMID- 32784053
OWN - NLM
STAT- MEDLINE
DCOM- 20210813
LR  - 20210813
IS  - 1532-3102 (Electronic)
IS  - 0143-4004 (Print)
IS  - 0143-4004 (Linking)
VI  - 99
DP  - 2020 Sep 15
TI  - Dysregulation of hypoxia-inducible factor-1alpha (Hif1alpha) expression in the 
      Hmox1-deficient placenta.
PG  - 108-116
LID - S0143-4004(20)30205-8 [pii]
LID - 10.1016/j.placenta.2020.07.015 [doi]
AB  - INTRODUCTION: Severe hypoxia exists in placentas during early pregnancy, with 
      reoxygenation during mid-gestation. Hypoxia-inducible factor-1alpha (Hif1alpha), an 
      oxygen sensor, initiates placental vascular development. We have shown that the 
      placental vasculature in Hmox1-deficient (Hmox1(+/-), Het) pregnancies is 
      impaired, with morphological defects similar to Hif1alpha-deficient placentas. 
      MATERIALS AND METHODS: Whole wild-type (WT) and Het mouse placentas were 
      collected at E8.5 (1%-3% O(2)) and E9.5-15.5 (8%-10% O(2)). mRNA levels were 
      determined using real-time RT-PCR or PCR arrays and protein levels using Western 
      blot. Bone marrow-derived macrophages (BMDMs) from WT, Het, and Hmox1 knockout 
      (KO) mice, representing different Hmox1 cellular levels, were generated to study 
      the role of Hmox1 on Hif1alpha 's response to hypoxia-reoxygenation and gestational 
      age-specific placental lysates. RESULTS: Hif1alpha was expressed in WT and Het 
      placentas throughout gestation, with protein levels peaking at E8.5 and mRNA 
      levels significantly upregulated from E9.5-E13.5, but significantly lower in Het 
      placentas. Genes associated with angiogenesis (Vegfa, Vegfr1, Mmp2, Cxcl12, 
      Angpt1, Nos3), antioxidants (Sod1, Gpx1), and transcription factors (Ap2, Bach1, 
      Nrf2) were significantly different in Het placentas. In response to in vitro 
      hypoxia-reoxygenation and to WT or Het placental lysates, Hif1alpha transcription was 
      lower in Het and Hmox1 KO BMDMs compared with WT BMDMs. DISCUSSION: These 
      findings suggest that deficiencies in Hmox1 underlie the insufficient placental 
      Hif1alpha response to hypoxia-reoxygenation during gestation and subsequently impair 
      downstream placental vascular formation. Therefore, a dysregulation of Hif1alpha 
      expression caused by any genetic defect or environmental influence in early 
      pregnancy could be the root cause of pregnancy disorders.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Zhao, Hui
AU  - Zhao H
AD  - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 
      94305, USA. Electronic address: huizhao2@stanford.edu.
FAU - Narasimhan, Purnima
AU  - Narasimhan P
AD  - Department of Obstetrics and Gynecology, Stanford University School of Medicine, 
      Stanford, CA, 94305, USA.
FAU - Kalish, Flora
AU  - Kalish F
AD  - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 
      94305, USA.
FAU - Wong, Ronald J
AU  - Wong RJ
AD  - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 
      94305, USA.
FAU - Stevenson, David K
AU  - Stevenson DK
AD  - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 
      94305, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200726
PL  - Netherlands
TA  - Placenta
JT  - Placenta
JID - 8006349
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Membrane Proteins)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (Hmox1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Female
MH  - *Gene Expression Regulation
MH  - Gestational Age
MH  - Heme Oxygenase-1/genetics/*metabolism
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Neovascularization, Physiologic/*physiology
MH  - Placenta/*metabolism
MH  - Pregnancy
MH  - Up-Regulation
MH  - Vascular Remodeling/physiology
PMC - PMC7549641
OTO - NOTNLM
OT  - Adverse pregnancy outcomes
OT  - Angiogenesis
OT  - Antioxidant
OT  - Hypoxia
OT  - Spiral artery remodeling
COIS- All the authors confirm that they have the guidance on competing interests and 
      none of the authors have any competing interests in the manuscript.
EDAT- 2020/08/14 06:00
MHDA- 2021/08/14 06:00
PMCR- 2020/09/15
CRDT- 2020/08/14 06:00
PHST- 2020/05/09 00:00 [received]
PHST- 2020/07/15 00:00 [accepted]
PHST- 2020/08/14 06:00 [pubmed]
PHST- 2021/08/14 06:00 [medline]
PHST- 2020/08/14 06:00 [entrez]
PHST- 2020/09/15 00:00 [pmc-release]
AID - S0143-4004(20)30205-8 [pii]
AID - 10.1016/j.placenta.2020.07.015 [doi]
PST - ppublish
SO  - Placenta. 2020 Sep 15;99:108-116. doi: 10.1016/j.placenta.2020.07.015. Epub 2020 
      Jul 26.