title: Cloprostenol, a prostaglandin F(2alpha) analog, induces hypoxia in rat placenta: BOLD contrast MRI.
abstract: Blood oxygen level dependent (BOLD) contrast was used to monitor hypoxia induced by cloprostenol, a prostaglandin F(2alpha) (PGF(2alpha)) analog, in the rat embryo-placental unit (EPU). It is shown that administration of cloprostenol (0.025 mg/rat) at mid-gestation (day 16) reduced EPU oxygenation, as detected by BOLD contrast MRI, in correlation with induction of vascular endothelial growth factor (VEGF) gene (Vegfa) expression in the corresponding placenta (r = 0.56, p = 0.03). Elevated VEGF mRNA expression in response to cloprostenol treatment was also observed at early gestation (day 9) in the forming placenta (p = 0.04) and uterus (p = 0.03). Cloprostenol increased the expression levels of endothelin-1 (ET-1) gene (Edn1) (p = 0.03) and its corresponding peptide (p = 0.02) in the forming placenta, as well as the expression of the endothelin receptor type A (ETA) gene (Ednra) in both the forming placenta (p = 0.009) and the uterus (p = 0.01). The levels of the endothelin receptor type B (ETB) gene (Ednrb) were not affected in response to cloprostenol, but a significant elevation in the expression level of this receptor was observed in the uterus at mid- and late gestation (day 22) (p = 0.04 and 0.01 respectively), suggesting a role for ETB in the vasodilatory status of the pregnant uterus. It is suggested that PGF(2alpha) induces uteroplacental vasoconstriction in the rat, and that ET-1 may take part in mediating this effect, probably via activation of ETA receptor. The uteroplacental vasoconstriction induces hypoxia, as manifested by significant changes in BOLD MRI and by upregulation of VEGF.
authors.affiliation: Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Girsh
authors.forename: Vicki
authors.initials: V
authors.lastname: Plaks
authors.forename: Assaf A
authors.initials: AA
authors.lastname: Gilad
authors.forename: Nava
authors.initials: N
authors.lastname: Nevo
authors.forename: Edna
authors.initials: E
authors.lastname: Schechtman
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
authors.forename: Nava
authors.initials: N
authors.lastname: Dekel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000187:drug effects*; D003008:Cloprostenol / Q000494:pharmacology / Q000633:toxicity*; D015237:Dinoprost / Q000502:physiology*; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D030762:Estrous Cycle; D005260:Female; D005311:Fetal Hypoxia / Q000139:chemically induced*; D005786:Gene Expression Regulation / Q000187:drug effects; D005865:Gestational Age; D006454:Hemoglobins / Q000032:analysis; D008279:Magnetic Resonance Imaging / Q000379:methods*; D010100:Oxygen / Q000097:blood; D010920:Placenta / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D044022:Receptor, Endothelin A / Q000096:biosynthesis / Q000235:genetics; D044023:Receptor, Endothelin B / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D014664:Vasodilation
chemical_list: D019332:Endothelin-1; D006454:Hemoglobins; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D003008:Cloprostenol; C100003:deoxyhemoglobin; D015237:Dinoprost; D010100:Oxygen