Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats.
Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats.
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DOI：
10.1161/hypertensionaha.115.06946
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Sathishkumar K
中科院分区：
文献类型：
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作者：
Gopalakrishnan K;Mishra JS;Chinnathambi V;Vincent KL;Patrikeev I;Motamedi M;Saade GR;Hankins GD;Sathishkumar K
母体睾酮水平升高会导致胎儿生长受限，最终导致男性比女性更明显的性别特异性成人高血压。在这项研究中，我们测试了子宫和胎儿胎盘紊乱是否是胎儿生长受限的基础，以及这些变化在男性和女性胎盘中是否存在差异。向妊娠Sprague-Dawley大鼠注射溶媒（n=16）或丙酸睾酮（从妊娠第15-19天开始，0.5 mg/Kg/天; n=16）。在妊娠第20天，我们使用微超声定量子宫动脉血流量，使用X射线微计算机断层扫描可视化胎盘动脉网络，使用哌莫硝唑和缺氧诱导因子-1 α确定胎儿胎盘缺氧，并使用Affyssin阵列确定胎盘血管发育相关基因表达的变化。注射睾酮的大鼠血浆睾酮水平增加2倍。睾丸激素升高的大鼠胎盘和胎仔重量较低。睾酮组子宫动脉血流量较低，阻力指数较高。睾酮组的桡动脉和螺旋动脉直径和长度、胎儿胎盘动脉分支数和脐动脉直径减少。此外，睾酮组胎盘和胎儿缺氧标志物升高。胎盘血管系统和缺氧的变化幅度在男性中大于女性，并且与参与血管生成和血管形态发生的独特基因组的性别特异性改变相关。结果表明，妊娠期睾酮水平升高会导致子宫动脉血流量减少和胎儿性别相关的子宫胎盘血管变化，这可能为成人发病疾病的后续性别差异奠定基础。
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 females. In this study, we tested whether utero- and feto-placental 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/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 testosterone group. Radial and spiral artery diameter and length, 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 were greater in males than females and were 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.