title: Chronic hypoxemia in late gestation decreases cardiomyocyte number but does not change expression of hypoxia-responsive genes.
abstract: BACKGROUND
  Placental insufficiency is the leading cause of intrauterine growth restriction in the developed world and results in chronic hypoxemia in the fetus. Oxygen is essential for fetal heart development, but a hypoxemic environment in utero can permanently alter development of cardiomyocytes. The present study aimed to investigate the effect of placental restriction and chronic hypoxemia on total number of cardiomyocytes, cardiomyocyte apoptosis, total length of coronary capillaries, and expression of genes regulated by hypoxia.
  
  
  RESULTS
  We induced experimental placental restriction from conception, which resulted in fetal growth restriction and chronic hypoxemia. Fetal hearts in the placental restriction group had fewer cardiomyocytes, but interestingly, there was no difference in the percentage of apoptotic cardiomyocytes; the abundance of the transcription factor that mediates hypoxia-induced apoptosis, p53; or expression of apoptotic genes Bax and Bcl2. Likewise, there was no difference in the abundance of autophagy regulator beclin 1 or expression of autophagic genes BECN1, BNIP3, LAMP1, and MAP1LC3B. Furthermore, fetuses exposed to normoxemia (control) or chronic hypoxemia (placental restriction) had similar mRNA expression of a suite of hypoxia-inducible factor target genes, which are essential for angiogenesis (VEGF, Flt1, Ang1, Ang2, and Tie2), vasodilation (iNOS and Adm), and glycolysis (GLUT1 and GLUT3). In addition, there was no change in the expression of PKC-ε, a cardioprotective gene with transcription regulated by hypoxia in a manner independent of hypoxia-inducible factors. There was an increased capillary length density but no difference in the total length of capillaries in the hearts of the chronically hypoxemic fetuses.
  
  
  CONCLUSIONS
  The lack of upregulation of hypoxia target genes in response to chronic hypoxemia in the fetal heart in late gestation may be due to a decrease in the number of cardiomyocytes (decreased oxygen demand) and the maintenance of the total length of capillaries. Consequently, these adaptive responses in the fetal heart may maintain a normal oxygen tension within the cardiomyocyte of the chronically hypoxemic fetus in late gestation.
authors.affiliation: Early Origins of Adult Health Research Group, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia (K.J.B., C.M.M., H.F., J.L.M.) Discipline of Physiology, School of Medical Science, The University of Adelaide, Adelaide, South Australia, Australia (K.J.B., C.M.M., J.L.M.).
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Botting
authors.affiliation: Early Origins of Adult Health Research Group, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia (K.J.B., C.M.M., H.F., J.L.M.) Discipline of Physiology, School of Medical Science, The University of Adelaide, Adelaide, South Australia, Australia (K.J.B., C.M.M., J.L.M.).
authors.forename: I Caroline
authors.initials: IC
authors.lastname: McMillen
authors.affiliation: Early Origins of Adult Health Research Group, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia (K.J.B., C.M.M., H.F., J.L.M.).
authors.forename: Heather
authors.initials: H
authors.lastname: Forbes
authors.affiliation: Stereology and EM Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, University of Aarhus, Denmark (J.R.N.).
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.affiliation: Early Origins of Adult Health Research Group, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia (K.J.B., C.M.M., H.F., J.L.M.) Discipline of Physiology, School of Medical Science, The University of Adelaide, Adelaide, South Australia, Australia (K.J.B., C.M.M., J.L.M.).
authors.forename: Janna L
authors.initials: JL
authors.lastname: Morrison
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D005260:Female; D018507:Gene Expression Regulation, Developmental; D019254:Genes, bcl-2 / Q000235:genetics; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010927:Placental Insufficiency / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism*; D012756:Sheep; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D052118:Lysosomal-Associated Membrane Protein 1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D052247:Nitric Oxide Synthase Type II
keywords: angiogenesis; apoptosis; hypoxia; myocytes; pregnancy
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