SEX STEROID HORMONES AND CALCITONIN GENE RELATED PEPTIDE

女性性激素对血管系统有深远的影响。几个 血管效应的机制已被提出。我们已经获得了 涉及感觉神经肽降钙素基因的新证据- 降钙素基因相关肽(CGRP)作为女性性激素的重要调节因子 类固醇在正常和妊娠患者心血管反应性中的作用 女性。在我们初步研究的基础上，我们提出了三个 相关假说：1)ES-传统醇和黄体酮调节 雌性(非妊娠和妊娠)大鼠神经元CGRP的表达 2)孕酮调节降钙素基因相关肽 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在雌性体内的表达和作用增强。 妊娠和降钙素基因相关肽具有代偿性血管扩张作用 妊娠期高血压。提出了三个具体的测试目标 这三个假设。具体目标1：确定是否 雌性大鼠背根神经节降钙素基因相关肽表达的变化 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 雌二醇孕酮对降钙素基因相关肽表达、神经生长的影响 使用a)活体动物模型和b)的NGF和NGF受体 原代培养背根神经节神经元。具体目标2：确定是否 性激素对降钙素基因相关肽血流动力学的调节作用 女性。我们将评估性类固醇激素对a)CGRP的影响。 诱发血流动力学改变和局部器官血流量 放射性微球技术，b)松弛响应性 血管对CGRP的抵抗，c)血管CGRP受体和受体后 转导途径。具体目标3：确定神经元是否 降钙素基因相关肽的表达及对血流动力学的影响 评估CGRP是否起到代偿血管扩张剂的作用 对妊娠高血压综合征患者血压升高的缓解作用 高血压。长期目标：这项提议将具有重要的基础 科学和临床意义。结果可能表明是否 性类固醇激素调节降钙素基因相关肽的表达及血流动力学 降钙素基因相关肽对女性的影响，也将有助于理解 降钙素基因相关肽在妊娠和妊娠中调节血管适应性中的作用 代偿性血流动力学用于减轻妊娠期高血压。 这些研究的结果将为今后的研究奠定基础 降钙素基因相关肽和性类固醇激素在病理生理中的作用 女性高血压和先兆子痫的风险。

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.