title: Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats.
abstract: Elevated maternal testosterone levels are shown to cause fetal growth restriction, eventually culminating in sex-specific adult-onset hypertension that is more pronounced in males than in females. In this study, we tested whether uteroplacental and fetoplacental disturbances underlie fetal growth restriction and if these changes vary in male and female placentas. Pregnant Sprague-Dawley rats were injected with vehicle (n=16) or testosterone propionate (0.5 mg/kg per day from gestation day 15-19; n=16). On gestation day 20, we quantified uterine artery blood flow using microultrasound, visualized placental arterial network using x-ray microcomputed tomography, determined fetoplacental hypoxia using pimonidazole and hypoxia-inducible factor-1α, and used Affymetrix array to determine changes in placental expression of genes involved in vascular development. Plasma testosterone levels increased 2-fold in testosterone-injected rats. Placental and fetal weights were lower in rats with elevated testosterone. Uterine artery blood flow was lower, and resistance index was higher in the testosterone group. Radial and spiral artery diameter and length, the number of fetoplacental arterial branches, and umbilical artery diameter were reduced in the testosterone group. In addition, markers of hypoxia in the placentas and fetuses were elevated in the testosterone group. The magnitude of changes in placental vasculature and hypoxia was greater in males than in females and was associated with sex-specific alteration of unique sets of genes involved in angiogenesis and blood vessel morphogenesis. The results demonstrate that elevated testosterone during gestation induces a decrease in uterine arterial blood flow and fetal sex-related uteroplacental vascular changes, which may set the stage for subsequent sex differences in adult-onset diseases.
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: Kathirvel
authors.initials: K
authors.lastname: Gopalakrishnan
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Mishra
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Chinnathambi
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Vincent
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: Igor
authors.initials: I
authors.lastname: Patrikeev
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: Massoud
authors.initials: M
authors.lastname: Motamedi
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: George R
authors.initials: GR
authors.lastname: Saade
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hankins
authors.affiliation: From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (K.G., J.S.M., V.C., K.L.V., G.R.S., G.D.H., K.S.) and Center for Biomedical Engineering (K.L.V., I.P., M.M.), University of Texas Medical Branch, Galveston. kusathis@utmb.edu.
authors.forename: Kunju
authors.initials: K
authors.lastname: Sathishkumar
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology*; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D010101:Oxygen Consumption / Q000502:physiology*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood*; D055988:Uterine Artery / Q000502:physiology*; D014599:Uterus / Q000098:blood supply / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D013739:Testosterone
keywords: hypoxia; placenta; preeclampsia; testosterone; vascular resistance