Developmental programming: influence of sex steroids and mechanisms

项目总结 胎儿发育关键期不利的宫内环境易使生物体 患高血压的风险增加。我们和其他人使用低蛋白(LP)的胎儿编程模型 证明后代的高血压与性别有关，男性的影响比女性更大，以及 内分泌变化可能是高血压发生的基础。中心假设是性行为 类固醇激素，睾酮(T)和雌二醇(E2)，通过与多种调节途径相互作用- 调控母系脂蛋白所致子代高血压的发生发展。 影响包括血管类固醇受体、内皮和平滑肌(VSM)功能的变化， 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： 性激素对低密度脂蛋白诱导的男性高血压母系发育的影响 以及雌性后代。具体目标1a。高血压的发病和严重程度是否与性别变化有关？ 类固醇？我们假设内分泌功能障碍会先于高血压的发展。 对男性的影响比对女性更明显。具体目标1b。是血压(BP)的改变 后代对性激素水平的变化有特异性吗？我们假设女性体内的OVX会加剧， 虽然男性的OCX抑制了高血压的发病和严重程度，但这些变化被以下因素逆转 分别使用类固醇替代药物和氟他胺。生长速度、肥胖度以及MAP和血浆T和 将对E2进行评估。具体目标2：内皮细胞和血管内皮细胞功能的特征及其 性类固醇对高血压后代的调节作用。我们假设内分泌功能障碍会改变 类固醇受体、内皮细胞和VSM功能在LP后代中的表达，这些影响是激素 具体的。具体目标2a。子代的血压变化是否与性激素水平的变化有关 受体？具体目标2b。血管内皮细胞功能是否改变并与T和E_2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 在高血压后代身上？具体目标2d。血管内皮细胞功能的改变和VSM是否特定于 高血压子代T和E_2水平的变化？具体目标3：血管RAS的特征 性激素对高血压子代的作用和调节。我们假设T和E_2的变化 在LP后代中，水平会改变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年龄的变化及其与T和E_2水平变化的关系 高血压后代？具体目标3b。RAS组分在超微结构中的表达和活性 在LP子代中，性腺切除对T和E_2的变化有特异性的紧张子代吗？该研究将评估是否 这些变化被各自的激素和氟他胺逆转。总而言之，这些研究将产生 有助于制定针对性别的高血压预防和治疗策略的重要见解。

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.