Mechanisms of uterine vascular adaptation in pregnancy

妊娠期子宫血管适应机制

基本信息

批准号：
7037567
负责人：
NATALIA I GOKINA
金额：
$ 29.59万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-04 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Normal pregnancy is characterized by a remarkable enhancement of uterine blood flow due to vasodilation and growth and remodeling of uterine vasculature that is associated with an increased uterine reactivity to vasoconstrictors. The long-term goal of this proposal is to understand the causes and cellular mechanisms underlying the modulation of uterine vascular contractility during gestation, with a specific focus on the role of ion channels in endothelial and vascular smooth muscle cells. Our central hypothesis is that pregnancy down- regulates the delayed rectifier and Ca2+-activated potassium channels with a resultant increase in Ca 2+ influx and smooth muscle contractility. Enhanced Ca 2+ sensitization of contractile process is a synergistical mechanism. Pregnancy-induced up-regulation of PKC and RhoA is proposed as a common regulatory mechanism for enhanced Ca 2+ sensitization and inhibition of K+ channel function. These adaptive changes are counteracted by increased Ca2+-dependent production of endothelium-derived NO and EDHF. Furthermore, we suggest that the effects of pregnancy are highly localized by the side of placentation and are mediated by estrogen. Specific Aim 1 will determine the mechanisms that regulate a steady state global [Ca2+]_ in smooth muscle of uterine resistance arteries, and their modulation in pregnancy. The role of PKC and RhoA in regulation of Ca 2+ sensitization and ion channel function will be studied. Specific Aim 2 will explore the mechanisms by which NO and EDHF mediates the effects of pregnancy on uterine arterial contractility with a specific focus on the role of endothelial intracellular Ca 2+ and small conductance Ca 2+-activated potassium channels. Specific Aim 3 will test the role of local vs. systemic factors, and of estrogen in mediating the effects of pregnancy on uterine artery function. The three Specific aims will integrate the physiological function (regulation of arterial diameter) with intracellular (Ca 2+ signaling, Ca 2+ sensitivity and ion channel function) and molecular (PKC and RhoA) mechanisms and will be accomplished by direct measurements of arterial diameter, intracellular Ca, membrane potential, expression and distribution of PKC and RhoA, and ion currents in endothelial and smooth muscle cells. The proposed study will provide new insights into cellular and molecular mechanisms mediating the effects of pregnancy and estrogen on uterine blood flow and significantly deepen the understanding how these mechanisms are altered in pregnancy-induced hypertension and preeclampsia.

描述（由申请人提供）：正常妊娠的特点是子宫血流显着增强，这是由于子宫血管舒张、生长和重塑，这与子宫对血管收缩剂的反应性增加有关。该提案的长期目标是了解妊娠期间子宫血管收缩力调节的原因和细胞机制，特别关注离子通道在内皮和血管平滑肌细胞中的作用。我们的中心假设是妊娠下调延迟整流和 Ca2+ 激活的钾通道，从而增加 Ca 2+ 流入和平滑肌收缩力。增强收缩过程的Ca 2+ 敏化是一种协同机制。妊娠诱导的 PKC 和 RhoA 上调被认为是增强 Ca 2+ 敏化和抑制 K+ 通道功能的常见调节机制。这些适应性变化被内皮源性 NO 和 EDHF 的 Ca2+ 依赖性生成增加所抵消。此外，我们认为妊娠的影响高度集中在胎盘一侧，并由雌激素介导。具体目标 1 将确定调节子宫阻力动脉平滑肌稳态全局 [Ca2+]_ 的机制及其在妊娠期间的调节。将研究PKC和RhoA在Ca 2+ 敏化和离子通道功能调节中的作用。具体目标 2 将探讨 NO 和 EDHF 介导妊娠对子宫动脉收缩力影响的机制，特别关注内皮细胞内 Ca 2+ 和小电导 Ca 2+ 激活钾通道的作用。具体目标 3 将测试局部因素与全身因素的作用，以及雌激素在调节妊娠对子宫动脉功能的影响中的作用。这三个具体目标将生理功能（动脉直径的调节）与细胞内（Ca 2+ 信号传导、Ca 2+ 敏感性和离子通道功能）和分子（PKC 和 RhoA）机制相结合，并将通过直接测量动脉直径来实现、细胞内 Ca、膜电位、PKC 和 RhoA 的表达和分布，以及内皮细胞和平滑肌细胞中的离子电流。拟议的研究将为介导妊娠和雌激素对子宫血流影响的细胞和分子机制提供新的见解，并显着加深对这些机制在妊娠高血压和先兆子痫中如何改变的理解。