Developmental programming: influence of sex steroids and mechanisms

描述（由申请方提供）：在胎儿发育的关键时期，不良的宫内环境易使生物体发生高血压的风险增加。我们和其他人使用胎儿编程的低蛋白（LP）模型表明，后代的高血压与性别有关，男性比女性的影响更大，内分泌变化可能是高血压发展的基础。中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的相互作用，调节母体LP诱导的高血压在后代中的发展和进展。影响包括血管类固醇受体、内皮和平滑肌（VSM）功能以及血管肾素血管紧张素系统（RAS）的变化。提出了三个具体目标。具体目标1：研究性类固醇对雄性和雌性后代中母体LP诱导的高血压发育起源的影响。具体目标1a。高血压的发生和严重程度与性类固醇激素的变化有关吗？我们假设内分泌功能障碍先于高血压的发展，男性比女性的影响更明显。 具体目标1b。后代血压（BP）的变化是否与性类固醇水平的变化有关？我们假设女性的OVX加重了高血压的发病和严重程度，而男性的OCX减轻了高血压的发病和严重程度，这些变化可通过相应的类固醇替代和氟替卡松逆转。将评估生长速率、肥胖和MAP以及血浆T和E2的变化。具体目标2：高血压后代中内皮和VSM细胞功能的特征及其通过性类固醇的调节。我们假设内分泌功能障碍会改变LP后代的类固醇受体、内皮细胞和VSM功能的表达，并且这些影响是激素特异性的。 具体目标2a。后代血压的变化是否与性类固醇受体水平的变化有关？ 具体目标2b。高血压后代内皮细胞功能是否改变并与T和E2水平变化相关？ 具体目标2c。高血压后代的VSM细胞功能是否改变并与T和E2水平的变化相关？具体目标2D。高血压后代内皮和VSM功能的改变是否与T和E2水平的变化有关？具体目标3：高血压后代血管RAS功能的特征和性类固醇的调节。我们假设T和E2水平的改变将改变LP后代RAS组分的表达和活性，从而改变BP。 具体目标3a. RAS的功能和表达是否随年龄而改变，是否与高血压后代T和E2水平的变化有关？ 具体目标3b.高血压后代RAS组分的表达和活性是否特异于LP后代性腺切除术后T和E2的变化？研究将评估这些变化是否被相应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，有助于制定预防和治疗高血压的性别特异性策略。 公共卫生相关性：成人健康和疾病的规划似乎取决于胎儿暴露于子宫内的各种环境因素。许多胎儿编程模型和人类流行病学数据表明，高血压易感性存在性别依赖性差异。这一建议将产生重要的见解，可以帮助制定针对性别的高血压预防和治疗策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Programming of adult health and disease appears to be dependent upon fetal exposure to various in utero environmental factors. Many models of fetal programming and epidemiological data in humans suggest gender-dependent variation in the susceptibility to hypertension. This proposal will yield important insights that could aid in the development of sex-specific strategies for the prevention and treatment of hypertension.