title: Chronic glucocorticoid exposure potentiates placental chorionic plate artery constriction: implications for aberrant fetoplacental vascular resistance in fetal growth restriction.
abstract: Fetal growth restriction (FGR) is a serious pregnancy complication, resulting in significant perinatal morbidity and mortality. Increased vascular resistance in the fetoplacental circulation is a hallmark of FGR and is associated with enhanced vasoconstriction of the resistance arteries in the placenta, the chorionic plate arteries (CPAs). Although the cause is unknown, FGR is associated with excess exposure to glucocorticoids (GCs), key mediators of vascular resistance in the systemic circulation. We hypothesized that GCs alter CPA reactivity, thereby contributing to the altered blood flow dynamics seen in FGR. We aimed to examine the acute and chronic effects of GCs on CPA reactivity and the operational mechanisms. Glucocorticoid receptors were highly expressed by CPA. 11β-Hydroxysteroid isoenzyme type 2 was detected within the endothelium, whereas 11β-hydroxysteroid isoenzyme type 1 was absent. Acute GC treatment significantly attenuated U46619-induced constriction. This effect was reversed by cotreatment with mifepristone or an endothelial NOS inhibitor. In contrast, chronic GC treatment potentiated U46619 constriction in a dose-dependent manner, which was partially abolished by mifepristone cotreatment. Similar effects were observed using a novel nonsteroidal glucocorticoid receptor-specific agonist. Chronic treatment with GCs altered the expression of several vasoactive factors, including thromboxane and bradykinin receptors, prokineticin-1, cyclooxygenase-2, and endothelial NOS. In summary, acute and chronic GC treatment exerts contrasting effects on CPA vasoreactivity. These opposing effects are consistent with temporal actions in other vascular beds and reflect activation of distinct nongenomic and genomic pathways. Chronic exposure to elevated GCs may contribute to the raised vascular resistance observed in the fetoplacental circulation in FGR.
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, St Mary's Hospital, Research Fifth Floor, Oxford Road, Manchester M13 9WL, United Kingdom.
authors.forename: J L
authors.initials: JL
authors.lastname: Nugent
authors.forename: M
authors.initials: M
authors.lastname: Wareing
authors.forename: V
authors.initials: V
authors.lastname: Palin
authors.forename: C P
authors.initials: CP
authors.lastname: Sibley
authors.forename: P N
authors.initials: PN
authors.lastname: Baker
authors.forename: D W
authors.initials: DW
authors.lastname: Ray
authors.forename: S N
authors.initials: SN
authors.lastname: Farrow
authors.forename: R L
authors.initials: RL
authors.lastname: Jones
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects; D002229:Carbenoxolone / Q000494:pharmacology; D002823:Chorion / Q000098:blood supply / Q000201:enzymology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D010920:Placenta / Q000098:blood supply*; D021041:Placental Circulation / Q000187:drug effects; D011247:Pregnancy; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D015735:Mifepristone; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003907:Dexamethasone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D006854:Hydrocortisone