Gestational Exposure to Elevated Testosterone Levels Induces Hypertension via Heightened Vascular Angiotensin II Type 1 Receptor Signaling in Rats
Gestational Exposure to Elevated Testosterone Levels Induces Hypertension via Heightened Vascular Angiotensin II Type 1 Receptor Signaling in Rats
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DOI：
10.1095/biolreprod.114.118968
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发表时间：
2014-07-01
影响因子：
3.6
通讯作者：
Sathishkumar, Kunju
中科院分区：
文献类型：
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作者：
Chinnathambi, Vijayakumar;More, Amar S.;Sathishkumar, Kunju
先兆子痫是一种危及生命的妊娠期疾病，其发病机制尚不清楚。患有先兆子痫和多囊卵巢综合征的孕妇血浆睾酮水平升高，这些孕妇经常发生妊娠高血压。我们检验了妊娠期睾酮水平升高通过血管紧张素II信号传导增强诱导高血压的假设。妊娠的Sprague-Dawley大鼠从Gestival第15天至第19天注射溶剂或丙酸睾酮，以诱导血浆睾酮水平增加2倍，与在临床病症如先兆子痫中观察到的水平相似。这两组大鼠中的一个亚组在睾酮暴露过程中通过管饲给予氯沙坦（一种血管紧张素II 1型受体拮抗剂）。通过颈动脉导管评估血压水平，通过钢丝肌造影评估内皮非依赖性血管反应性。还检查了血浆中的血管紧张素II水平和肠系膜动脉中的血管紧张素II 1型受体表达。孕激素给药组第20天的血压水平显著高于对照组。在睾酮暴露过程中使用氯沙坦治疗可显著减弱睾酮诱导的高血压。对照组和睾酮治疗组大鼠的血浆血管紧张素II水平无显著差异;然而，睾酮水平升高显著增加肠系膜动脉血管紧张素II 1型受体蛋白水平。在睾酮治疗的大鼠，肠系膜动脉收缩反应血管紧张素II显着更大，而收缩反应K+去极化和苯肾上腺素不受影响。结果表明，妊娠期睾酮水平升高通过增强血管紧张素II 1型受体介导的信号传导诱导妊娠大鼠高血压，提供了一种将母体睾酮水平升高与妊娠期高血压联系起来的分子机制。
Pre-eclampsia is a life-threatening pregnancy disorder whose pathogenesis remains unclear. Plasma testosterone levels are elevated in pregnant women with pre-eclampsia and polycystic ovary syndrome, who often develop gestational hypertension. We tested the hypothesis that increased gestational testosterone levels induce hypertension via heightened angiotensin II signaling. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate from Gestational Day 15 to 19 to induce a 2-fold increase in plasma testosterone levels, similar to levels observed in clinical conditions like preeclampsia. A subset of rats in these two groups was given losartan, an angiotensin II type 1 receptor antagonist by gavage during the course of testosterone exposure. Blood pressure levels were assessed through a carotid arterial catheter and endothelium-independent vascular reactivity through wire myography. Angiotensin II levels in plasma and angiotensin II type 1 receptor expression in mesenteric arteries were also examined. Blood pressure levels were significantly higher on Gestational Day 20 in testosterone-treated dams than in controls. Treatment with losartan during the course of testosterone exposure significantly attenuated testosterone-induced hypertension. Plasma angiotensin II levels were not significantly different between control and testosterone-treated rats; however, elevated testosterone levels significantly increased angiotensin II type 1 receptor protein levels in the mesenteric arteries. In testosterone-treated rats, mesenteric artery contractile responses to angiotensin II were significantly greater, whereas contractile responses to K+ depolarization and phenylephrine were unaffected. The results demonstrate that elevated testosterone during gestation induces hypertension in pregnant rats via heightened angiotensin II type 1 receptor-mediated signaling, providing a molecular mechanism linking elevated maternal testosterone levels with gestational hypertension.