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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-1?, 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.

SUBMITTER: Gopalakrishnan K

PROVIDER: S-EPMC4752400 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats.

Gopalakrishnan Kathirvel K Mishra Jay S JS Chinnathambi Vijayakumar V Vincent Kathleen L KL Patrikeev Igor I Motamedi Massoud M Saade George R GR Hankins Gary D GD Sathishkumar Kunju K

Hypertension (Dallas, Tex. : 1979) 20160118 3

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; ...[more]

PMID: 26781277

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Project description:BackgroundPre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood.MethodsHuman placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague-Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors.ResultsIn this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFβ1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats.ConclusionsOur data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization.

Dataset Information

Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats.

Publications

Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats.

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