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）：正常妊娠的特征是由于血管舒张，生长以及子宫脉管结构的生长以及重塑与子宫对血管收缩剂的反应增加有关。该提案的长期目标是了解妊娠过程中子宫血管收缩性调节的原因和细胞机制，并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，怀孕降低了延迟的整流器和Ca2+激活的钾通道，导致Ca 2+膨胀和平滑肌收缩性的增加。增强收缩过程的Ca 2+敏化是一种协同机制。妊娠引起的PKC和RHOA的上调被提出是增强Ca 2+敏化和K+通道功能抑制的常见调节机制。这些适应性变化被CA2+依赖性的NO和EDHF的产生增加而抵消。此外，我们建议妊娠的作用在胎盘侧高度局部，并由雌激素介导。具体目标1将确定在子宫抗动脉平滑肌中调节稳态全球[Ca2+] _的机制，并在怀孕中调节。 PKC和RHOA在调节Ca 2+敏化和离子通道功能中的作用将被研究。具体目标2将探讨NO和EDHF介导妊娠对子宫动脉收缩力的影响的机制，并特别关注内皮细胞内Ca 2+的作用，而小型电导Ca 2+激活的钾通道。具体目标3将测试局部因素与系统因素的作用，以及雌激素在介导妊娠对子宫动脉功能的影响中的作用。这三个特定目的将与细胞内（Ca 2+信号传导，Ca 2+敏感性和离子通道功能）和分子（PKC和RhoA）机制相结合的生理功能（动脉直径调节），并将通过直接测量动脉直径，细胞内CA，膜内，膜型和RhoA的表达和RHOA，以及PKC的表达和RHOA，以及直接测量PKC和RHOA，以及PKC的表达和RHOA的分布，肌肉细胞。拟议的研究将为介导妊娠和雌激素对子宫血流的影响的细胞和分子机制提供新的见解，并显着加深理解这些机制在怀孕引起的高血压和前启示性启发前的改变。