Sathishkumar Kunju, Balakrishnan Meena P, Yallampalli Chandrasekhar
Department of Obstetrics & Gynecology, The University of Texas Medical Branch, Galveston, Texas.
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.
Biol Reprod. 2015 Feb;92(2):55. doi: 10.1095/biolreprod.114.126482. Epub 2014 Dec 30.
Gestational protein restriction results in intrauterine growth restriction and hypertension in adult female growth-restricted rats. Enhanced vascular responsiveness to angiotensin II is observed, and blockade of the renin-angiotensin system abolishes hypertension in adult growth-restricted rats, suggesting that the renin-angiotensin system contributes to intrauterine growth restriction-induced hypertension. Moreover, growth-restricted adult rats have higher plasma testosterone levels, and antiandrogen treatment abolishes hypertension, indicating an important role for testosterone. We hypothesized that androgens may play a pivotal role in the enhanced responsiveness to Ang II and hypertension. Female offspring of pregnant rats fed 20% protein (control) or 6% protein diet (protein restricted), at 6 mo of age, were studied. Plasma testosterone and mean arterial pressure in protein-restricted offspring were significantly higher compared to controls. Flutamide treatment (10 mg/kg/day subcutaneously for 10 days) reduced mean arterial pressure in protein-restricted offspring but was without significant effect in controls. Vascular Agtr1/Agtr2 ratio was significantly higher in protein-restricted offspring, an effect that was reversed by flutamide. Flutamide treatment did not have any effect on Agtr1/Agtr2 ratio in controls. Enhanced contractile response to angiotensin II in mesenteric arteries was observed in protein-restricted offspring compared with control. Flutamide treatment reversed the enhanced contractile response to angiotensin II in protein-restricted offspring without significant effect in controls. Vascular reactivity to phenylephrine was similar between the control and protein-restricted offspring with and without flutamide treatment, suggesting that enhanced contractile response and flutamide's reversal effect is specific to angiotensin II. These results suggest that prenatally protein-restricted rats exhibit an enhanced responsiveness to angiotensin II that is testosterone-dependent.
孕期蛋白质限制会导致成年雌性生长受限大鼠出现宫内生长受限和高血压。观察到血管对血管紧张素II的反应性增强，并且阻断肾素-血管紧张素系统可消除成年生长受限大鼠的高血压，这表明肾素-血管紧张素系统促成了宫内生长受限诱导的高血压。此外，生长受限的成年大鼠血浆睾酮水平较高，抗雄激素治疗可消除高血压，这表明睾酮起重要作用。我们推测雄激素可能在对血管紧张素II的反应性增强和高血压中起关键作用。对孕期分别喂食20%蛋白质（对照）或6%蛋白质饮食（蛋白质限制）的大鼠所产雌性后代在6月龄时进行了研究。与对照组相比，蛋白质限制组后代的血浆睾酮和平均动脉压显著更高。氟他胺治疗（皮下注射10mg/kg/天，持续10天）降低了蛋白质限制组后代的平均动脉压，但对对照组无显著影响。蛋白质限制组后代的血管Agtr1/Agtr2比值显著更高，氟他胺可逆转这一效应。氟他胺治疗对对照组的Agtr1/Agtr2比值无任何影响。与对照组相比，蛋白质限制组后代的肠系膜动脉对血管紧张素II的收缩反应增强。氟他胺治疗逆转了蛋白质限制组后代对血管紧张素II增强的收缩反应，而对对照组无显著影响。无论有无氟他胺治疗，对照组和蛋白质限制组后代对去氧肾上腺素的血管反应性相似，这表明增强的收缩反应和氟他胺的逆转效应是血管紧张素II特有的。这些结果表明，产前蛋白质限制的大鼠对血管紧张素II的反应性增强，且这种增强依赖于睾酮。
