SEX STEROID HORMONES AND CALCITONIN GENE RELATED PEPTIDE

性类固醇激素及降钙素基因相关肽

• 批准号: 6330126
• 负责人: CHANDRASEKHAR YALLAMPALLI
• 金额: $ 32.57万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-20 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330126
• 关键词: calcitonin gene related peptide; estradiol; female; gene induction /repression; growth factor receptors; hormone regulation /control mechanism; laboratory rat; neurotrophic factors; pregnancy toxemia /hypertension; progesterone; spinal ganglion; tissue /cell culture; vasodilation

Female sex steroids profoundly influence the vascular system. Several mechanisms have been proposed for the vascular effects. We have obtained new evidence which implicates sensory neuropeptide calcitonin gene- related peptide (CGRP) as an important modulator of the female sex steroid actions in cardiovascular reactivity in normal and pregnant females. Based upon our preliminary studies, we propose three interrelated hypotheses: 1) es-tradiol and progesterone regulate neuronal CGRP expression in female (nonpregnant and pregnant) rats which in turn influence vascular tone, 2) progesterone modulates the CGRP effector systems, the mechanism of which is through the upregulation of vascular CGRP receptors, and thus modulates vasodilator actions of CGRP, 3) the expression and effects of CGRP in females are enhanced during pregnancy and CGRP plays a compensatory vasodilator role to attenuate hypertension during pregnancy. Three specific aims are proposed to test these three hypotheses. Specific Aim 1: To determine whether alterations in CGRP expression in female rat dorsal root ganglia (DRG) are related to changes in sex steroid hormones and to investigate the mechanisms involved. We will determine the effects of steroid hormones estradiol and progesterone on the expression of CGRP, nerve growth factor (NGF) and NGF receptors using a) in vivo animal models and b) primary cultures of DRG neurons. Specific Aim 2: To determine whether sex steroid hormones modulate the hemodynamic effects of CGRP in females. We will assess the effects of sex steroid hormones on a) CGRP- induced hemodynamic changes and regional organ blood flow using radioactive microsphere technique, b) relaxation responsiveness of resistance vessels to CGRP, c) vascular CGRP receptors and postreceptor transduction pathway. Specific Aim 3: To determine whether neuronal CGRP expression and the hemodynamic effects of CGRP are altered during pregnancy and evaluate whether CGRP plays a compensatory vasodilator role to attenuate the elevated blood pressure during pregnancy-induced hypertension. Long-term goals: This proposal will have important basic scientific and clinical implications. The results may indicate whether sex steroid hormones regulate the expression of CGRP and the hemodynamic effects of CGRP in females and will also help to understand the role of CGRP in modulating vascular adaptations during pregnancy and in compensatory hemodynamics to attenuate hypertension during pregnancy. The results of these studies would lay the foundation for future studies of involvement of CGRP and sex steroid hormones in the pathophysiology of hypertension in females and preeclampsia.

女性性类固醇对血管系统有深远的影响。一些 已经提出了血管效应的机制。我们已经获得了 涉及感觉神经肽降钙素基因的新证据- 相关肽（CGRP）作为女性性别的重要调节剂 类固醇对正常人和孕妇心血管反应的作用 女性。 根据我们的初步研究，我们提出了三个建议 相互关联的假设：1）雌二醇和黄体酮调节 雌性（非妊娠和妊娠）大鼠神经元 CGRP 表达 进而影响血管张力，2) 黄体酮调节 CGRP 效应系统，其机制是通过上调 血管 CGRP 受体，从而调节 CGRP 的血管舒张作用， 3) CGRP在女性体内的表达和作用增强 妊娠及CGRP发挥代偿性血管扩张作用以减弱 怀孕期间的高血压。 提出了三个具体目标来测试 这三个假设。 具体目标 1：确定是否 雌性大鼠背根神经节（DRG）CGRP表达的变化 与性类固醇激素的变化有关，并调查 涉及的机制。 我们将确定类固醇激素的影响 雌二醇和孕酮对 CGRP 表达、神经生长的影响 使用 a) 体内动物模型和 b) 检测因子 (NGF) 和 NGF 受体 DRG 神经元的原代培养物。 具体目标 2：确定是否 性类固醇激素调节 CGRP 的血流动力学效应 女性。 我们将评估性类固醇激素对 a) CGRP- 的影响 使用诱导血流动力学变化和局部器官血流 放射性微球技术，b) 的弛豫反应性 血管对 CGRP 的抵抗，c) 血管 CGRP 受体和后受体 转导途径。 具体目标 3：确定神经元是否 CGRP 表达和 CGRP 的血流动力学效应在 妊娠并评估 CGRP 是否发挥代偿性血管扩张作用 具有减轻妊娠期间血压升高的作用 高血压。 长期目标：该提案将具有重要的基础 科学和临床意义。 结果可能表明是否 性类固醇激素调节 CGRP 的表达和血流动力学 CGRP 对女性的影响，也将有助于了解 CGRP 在怀孕期间和怀孕期间调节血管适应 代偿血流动力学以减轻妊娠期高血压。 这些研究的结果将为未来的研究奠定基础 CGRP 和性类固醇激素参与病理生理学的研究 女性高血压和先兆子痫。