Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus.
Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130-135 (n = 19) and 139-145 (n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-α and -β protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-β1, IL-1β, and β2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain (PHD)2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia-inducible factor-1α (HIF-1α) and HIF-1β mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung.
Molecular and Evolutionary Physiology of the Lung Laboratory, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
Sandra
S
Orgeig
Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia; Molecular and Evolutionary Physiology of the Lung Laboratory, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
Erin V
http://orcid.org/0000-0002-9849-5958
EV
McGillick
Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia;
Kimberley J
KJ
Botting
Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia;
Song
S
Zhang
Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia;
I Caroline
IC
McMillen
Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia; Janna.Morrison@unisa.edu.au.
Janna L
http://orcid.org/0000-0002-8602-8519
JL
Morrison
D000818:Animals; D047109:Fetal Development; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000473:pathology*; D005311:Fetal Hypoxia / Q000473:pathology*; D050993:GATA6 Transcription Factor / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D006854:Hydrocortisone / Q000097:blood; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000196:embryology* / Q000201:enzymology; D064828:Prolyl Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011941:Receptors, Adrenergic / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012756:Sheep / Q000235:genetics; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D050993:GATA6 Transcription Factor; D005938:Glucocorticoids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D037663:Pulmonary Surfactant-Associated Protein D; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D011965:Receptors, Glucocorticoid; D053773:Transforming Growth Factor beta1; D064828:Prolyl Hydroxylases; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D006854:Hydrocortisone
chronic hypoxia; fetus; prolyl hydroxylase; surfactant