Vascular AT2R expression and function during pregnancy

妊娠期间血管AT2R的表达和功能

基本信息

批准号：
9981801
负责人：
SATHISH KUMAR
金额：
$ 38.25万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981801
关键词：
Address Affect Agonist Angiotensin II Animals Antihypertensive Agents Arteries Biological Assay Blood Blood Pressure Blood Vessels Blood flow Cardiovascular system Clinical Data Dimensions Disease Dose Down-Regulation EMSA Endothelial Cells Endothelium Epoprostenol Equilibrium Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogen receptor positive Estrogens Europe Failure Fetus Functional disorder Genetic Transcription Growth Human Hypertension Intervention Studies Ligand Binding Measurement Measures Mediating Membrane Potentials Mesenteric Arteries Metabolic Modeling Molecular Mothers Mus Nitrates Nitrites Nutrient Oral Organ Pathway interactions Patients Peptides Perfusion Placenta Play Pre-Eclampsia Pregnancy Pregnant Women Process Production Rattus Receptor Activation Receptor, Angiotensin, Type 1 Relaxation Reporter Research Response Elements Rodent Model Role Signal Transduction Small Interfering RNA Solid System Systemic blood pressure Tail Testing Therapeutic Therapeutic Uses Translating Type 2 Angiotensin II Receptor Up-Regulation Uterus Vascular Diseases Vascular Smooth Muscle Vascular resistance Vascularization Vasoconstrictor Agents Vasodilation base blood pressure reduction clinically relevant endothelial dysfunction fetal improved in vivo knock-down novel novel therapeutics oxygen transport pregnancy hypertension pregnant promoter receptor receptor expression receptor function receptor upregulation response targeted treatment transcription factor translational study vasoconstriction

项目摘要

ABSTRACT In pregnancy, endothelial vasodilation is enhanced to decrease blood pressure and increase uterine blood flow. Pregnancy-enhanced vasodilatory function is achieved through an increase in expression of angiotensin type 2 receptor (AT2R) in the endothelium of uterine and systemic vasculature. In preeclampsia, this adaptive endothelial response fails due to downregulation of AT2R expression and activity, with associated endothelial dysfunction, increased vascular resistance, and hypertension. Preeclampsia affects 5%–8% of all pregnancies, and treatment is limited to antihypertensives that relax vascular smooth muscle. There is no treatment to directly address endothelial failure. The cause of preeclampsia is not known, but the pregnancy-specific upregulation of AT2R in the vasculature may hold important keys to understanding the origins of the disease and the underlying causes of maternal organ function. The opportunity to study the effects of novel oral nonpeptide Compund21 is significant and valuable. Based on solid preliminary data, we propose that pregnancy selectively upregulates endothelial AT2R via differential binding of ligand-activated estrogen receptor (ie, ERβ vs ERα) to a functional estrogen response element (ERE) in the AT2R promoter. Failure of vascular AT2R upregulation during pregnancy plays a role in endothelial cell dysfunction and vasoconstriction in preeclampsia and, consequently, activation of this system reverses preeclamptic vascular dysfunction. Aim 1 will first establish pregnancy-specific upregulation of AT2R in the endothelium and then define the mechanistic role of ER α or β in upregulation of AT2R by using ER-specific agonists, antagonists, and siRNA in rodent models. AT2R transcription mechanisms will determine differential binding of ligand- activated ER and transcription factors to putative ERE in AT2R promoter in primary human uterine artery endothelial cells, using ChiP and EMSA/ supershift assays, and then use reporter assays to determine their functionality. Aim 2 will move towards clinical translational relevance. We will determine if vascular AT2R is involved in preeclamptic endothelial dysfunction and if AT2R activation rescues vascular dysfunction. To test the AT2R-mediated mechanisms, EDHF, NO, and PGI2 pathways of vascular relaxation pathways will be determined. Also, the expression of eNOS and its activity state—signaling components of EDHF and PGI2 pathways as well as nitrate/ nitrite and PGI2 production and changes in membrane potential—will be measured. Aim 3 will verify the AT2R effects in vivo. We will use 2 models of gestational hypertension to test the effect of 2 selective AT2R agonists (CGP-42112 peptide and Compound 21) on the maternal, placental, and fetal abnormalities associated with preeclampsia. These studies will provide new information of how pregnancy increases endothelial AT2R and that failure of this process leads to preeclamptic endothelial dysfunction. The positive translational significance of these aims is that they evaluate the therapeutic utility of an endothelium- targeted therapy which is potentially safe in preeclampsia subjects.

抽象的在怀孕期间，内皮血管舒张增强，从而降低血压并增加子宫血流量。妊娠增强的血管舒张功能是通过增加 2 型血管紧张素的表达来实现的子宫内皮和全身脉管系统中的受体（AT2R）在先兆子痫中具有适应性。由于 AT2R 表达和活性下调，内皮反应失败，并伴有相关的内皮细胞功能障碍、血管阻力增加和先兆子痫影响着 5%–8% 的妊娠，治疗仅限于放松血管平滑肌的抗高血压药物，目前尚无治疗方法。直接解决先兆子痫的原因尚不清楚，但妊娠特异性。脉管系统中 AT2R 的上调可能是了解疾病起源的重要关键以及母体器官功能的根本原因。有机会研究新型口腔的影响。基于可靠的初步数据，我们认为非肽化合物 21 具有重要意义和价值。妊娠通过配体激活雌激素的差异结合选择性上调内皮 AT2R AT2R 启动子中功能性雌激素反应元件 (ERE) 的受体（即 ERβ 与 ERα）的失败。妊娠期间血管 AT2R 上调在内皮细胞功能障碍中发挥作用先兆子痫的血管收缩，因此，该系统的激活可以逆转先兆子痫的血管收缩目标 1 首先在内皮细胞中建立妊娠特异性 AT2R 上调，然后建立内皮细胞 AT2R 功能障碍。通过使用 ER 特异性激动剂、拮抗剂和拮抗剂，定义 ER α 或 β 在 AT2R 上调中的机制作用啮齿动物模型中的 siRNA 将决定配体的差异结合。激活 ER 和转录因子至人原代子宫动脉 AT2R 启动子中推定的 ERE 内皮细胞，使用 ChiP 和 EMSA/supershift 检测，然后使用报告检测来确定它们目标 2 将转向临床转化相关性我们将确定血管 AT2R 是否具有功能性。涉及先兆子痫内皮功能障碍以及 AT2R 激活是否可以挽救血管功能障碍。 AT2R介导的机制，血管舒张途径的EDHF、NO和PGI2途径将是此外，还确定了 eNOS 的表达及其活性状态——EDHF 和 PGI2 的信号成分。途径以及硝酸盐/亚硝酸盐和 PGI2 的产生以及膜电位的变化 - 将目标3将验证AT2R的体内效果，我们将使用2种妊娠高血压模型进行测试。 2 种选择性 AT2R 激动剂（CGP-42112 肽和化合物 21）对母体、胎盘和胎儿的影响这些研究将提供与先兆子痫相关的胎儿畸形的新信息。增加内皮 AT2R，该过程失败会导致先兆子痫内皮功能障碍。这些目标的积极转化意义在于它们评估了内皮细胞的治疗效用靶向治疗对于先兆子痫受试者可能是安全的。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Estrogen Receptor-β Mediates Estradiol-Induced Pregnancy-Specific Uterine Artery Endothelial Cell Angiotensin Type-2 Receptor Expression.

雌激素受体-β 介导雌二醇诱导妊娠特异性子宫动脉内皮细胞血管紧张素 2 型受体表达。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Mishra, Jay S;Te Riele, Gigi M;Qi, Qian;Lechuga, Thomas J;Gopalakrishnan, Kathirvel;Chen, Dong;Kumar, Sathish
通讯作者：
Kumar, Sathish

Hypoxia-induced small extracellular vesicle proteins regulate proinflammatory cytokines and systemic blood pressure in pregnant rats.

缺氧诱导的小细胞外囊泡蛋白调节妊娠大鼠的促炎细胞因子和全身血压。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Dutta, Suchismita;Lai, Andrew;Scholz;Shiddiky, Muhammad J A;Yamauchi, Yusuke;Mishra, Jay S;Rice, Gregory E;Hyett, Jon;Kumar, Sathish;Salomon, Carlos
通讯作者：
Salomon, Carlos

Testosterone plays a permissive role in angiotensin II-induced hypertension and cardiac hypertrophy in male rats.

睾酮在血管紧张素 II 诱导的雄性大鼠高血压和心脏肥大中发挥许可作用。