SEX STEROID HORMONES AND CALCITONIN GENE RELATED PEPTIDE

女性性类固醇对血管系统有着深刻的影响。几 已经提出了血管效应的机制。我们所获得 新的证据表明，感觉神经肽降钙素基因- 相关肽（CGRP）作为一种重要的调节剂的女性 激素对正常人和孕妇心血管反应性影响 女性 根据我们的初步研究，我们提出了三个 相关假设：1）雌二醇和孕酮调节 雌性大鼠（非妊娠和妊娠）的神经元CGRP表达， 反过来影响血管张力，2）孕酮调节CGRP 效应系统，其机制是通过上调 血管CGRP受体，从而调节CGRP的血管扩张作用， 3)CGRP在雌性中的表达和作用在 妊娠和CGRP起着代偿性血管扩张作用， 妊娠期高血压。 提出了三个具体目标来测试 这三个假设。 具体目标1：确定 雌性大鼠背根神经节CGRP表达的变化 与性类固醇激素的变化有关， 涉及的机制。 我们将确定类固醇激素的作用 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） DRG神经元的原代培养物。 具体目标2：确定 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- 诱导的血流动力学变化和局部器官血流量， 放射性微球技术，B） c）血管CGRP受体和受体后受体 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心肌缺血时改变， 评估CGRP是否起代偿性血管扩张作用 作用，以减轻血压升高，在妊娠诱导 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， 性类固醇激素调节CGRP的表达和血流动力学 CGRP在女性中的作用，也将有助于了解 降钙素基因相关肽在调节妊娠期血管适应性和妊娠期高血压疾病中的作用 代偿性血流动力学以减轻妊娠期高血压。 这些研究结果将为今后的研究奠定基础 CGRP和性类固醇激素在病理生理学中的参与 女性高血压和先兆子痫。

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.