Developmental programming: influence of sex steroids and mechanisms

项目摘要 在胎儿发育的关键时期，不利的宫内环境使生物体易于 增加患高血压的风险。我们和其他人使用胎儿编程的低蛋白（LP）模型 证明后代的高血压与性别有关，对男性的影响大于女性， 内分泌的改变可能是高血压的成因。核心假设是性 类固醇激素，睾酮（T）和雌二醇（E2），通过与各种调节途径相互作用， 通过多种途径，调节母体脂蛋白性高血压在子代的发生和发展。 影响包括血管类固醇受体、内皮和平滑肌（VSM）功能的变化， 和血管肾素血管紧张素系统（RAS）。提出了三个具体目标。具体目标1： 性类固醇激素对高血压母源性发育的影响 和女性后代。具体目标1a。高血压的发病和严重程度是否与性别的改变有关 类固醇？我们假设内分泌功能障碍先于高血压的发展， 对男性的影响比女性更明显。具体目标1b。血压（BP）的变化是否与 后代对性类固醇水平的变化有何反应我们假设女性卵巢切除会加重， 而男性的OCX减弱，高血压的发病和严重程度，这些变化被逆转， 类固醇替代和氟替卡松。生长速度、肥胖、MAP和血浆T变化， 将对E2进行评估。具体目标2：内皮和VSM细胞功能的表征及其 高血压后代中性类固醇的调节。我们假设内分泌失调会改变 类固醇受体的表达，内皮细胞和VSM功能在LP后代，这些影响是激素 特定.具体目标2a。后代血压的变化是否与性类固醇水平的变化有关 受体？具体目标2b。内皮细胞功能是否改变并与T和E2水平的变化有关？ 高血压后代？具体目标2c。VSM细胞功能是否改变并与T和E2水平的变化有关 在高血压的后代？具体目标2D。内皮细胞和VSM功能的改变是否是 高血压后代T和E2水平的变化？具体目标3：血管RAS的表征 性激素在高血压后代中的作用和调节。我们假设T和E2的改变 水平将改变LP后代中RAS组分的表达和活性，从而改变BP。具体目标3a.是 RAS组分的功能和表达随着年龄的增长而改变，并与T和E2水平的变化有关。 高血压的后代吗具体目标3b. RAS组分的表达和活性是否与高血压相关？ 在LP后代中使用性腺切除术对T和E2变化有特异性的紧张后代？该研究将评估 这些变化被各自的激素和氟替卡松逆转。总的来说，这些研究将产生 重要的见解，可以帮助制定预防和治疗高血压的性别特异性策略。

PROJECT SUMMARY Adverse intrauterine environment during the critical period of fetal development predisposes organisms to increased risk for developing hypertension. We and others using a low-protein (LP) model of fetal programming demonstrated that hypertension in offspring is gender related, with a greater effect in males than females, and endocrine changes may underlie the development of hypertension. The central hypothesis is that sex steroid hormones, testosterone (T) and estradiol (E2), via interaction with a variety of regulatory path- ways, regulate the development and progression of maternal LP-induced hypertension in the offspring. Effects include changes in vascular steroid receptors, endothelial and smooth muscle (VSM) function, and vascular rennin angiotensin system (RAS). Three specific aims are proposed. Specific Aim 1: Investigate the influence of sex steroids on maternal LP-induced developmental origins of hypertension in male and female offspring. Specific Aim 1a. Is the onset and severity of hypertension related to changes in sex steroids? We hypothesize that endocrine dysfunction will precede the development of hypertension with a more pronounced effect in males than females. Specific Aim 1b. Are alterations in blood pressure (BP) in the offspring specific to changes in the levels of sex steroids? We hypothesize that OVX in females exacerbates, while OCX in males dampens, the onset and severity of hypertension, and these changes are reversed by respective steroid replacement and flutamide. Growth rate, adiposity, and changes in MAP and plasma T and E2 will be assessed. Specific Aim 2: Characterization of endothelial and VSM cell functions and their regulation by sex steroids in hypertensive offspring. We hypothesize that endocrine dysfunction will alter expression of steroid receptors, endothelial, and VSM functions in LP offspring, and these effects are hormone specific. Specific Aim 2a. Are alterations in BP in the offspring specific to changes in the levels of sex steroid receptors? Specific Aim 2b. Is endothelial cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2c. Is VSM cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2d. Are alterations in the function of endothelium and VSM specific to changes in T and E2 levels in hypertensive offspring? Specific Aim 3: Characterization of vascular RAS function and regulation by sex steroids in hypertensive offspring. We hypothesize that alteration in T and E2 levels will alter expression and activity of RAS components, and thus BP, in LP offspring. Specific Aim 3a. Is the function and expression of RAS components altered with age and related to changes in T and E2 levels in the hypertensive offspring? Specific Aim 3b. Are the expression and activity of RAS components in hyper- tensive offspring specific to changes in T and E2 using gonadectomy in LP offspring? The study will assess if these changes are reversed with respective hormones and flutamide. Collectively, these studies will yield important insights that could aid in developing sex-specific strategies for preventing and treating hypertension.