Vascular Interactions of Estrogen Receptor GPR30 and the Renin-Angiotensin System

雌激素受体 GPR30 和肾素-血管紧张素系统的血管相互作用

• 批准号: 8529601
• 负责人: Sarah H. Lindsey
• 金额: $ 22.94万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529601
• 关键词: 8-Bromo Cyclic Adenosine Monophosphate; AGTR2 gene; Acute; Address; Adenylate Cyclase; Adrenergic Receptor; Affinity; Aftercare; Age; Agonist; Angiotensins; Animals; Antibodies; Antihypertensive Agents; Antisense Oligonucleotides; Aorta; Arteries; Attenuated; Benefits and Risks; Binding; Blood Pressure; Blood Vessels; Caffeine; Cardiovascular Diseases; Cardiovascular system; Cell Culture System; Cells; Choline Chloride; Chronic; Clinical Research; Clinical Trials; Confocal Microscopy; Contractile Proteins; Contracts; Culture Media; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Dependence; Development; Diet; Dose; Down-Regulation; Endothelin; Endothelin A Receptor; Enzymes; Equilibrium; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogen Replacements; Estrogens; Estrus; Evolution; Exposure to; Female; Formalin; Forskolin; Freezing; Funding; Fura-2; G-Protein-Coupled Receptors; Gender; Gene Expression; Genomics; Health; Hormone replacement therapy; Hormones; Human; Hypertension; Hypotension; Image; Immunoblotting; Immunohistochemistry; In Vitro; Incidence; Incubated; Injury; Institution; Kidney; Laboratories; Lasers; Life; Losartan; Measurement; Measures; Mediating; Menopause; Mentors; Mesenteric Arteries; Mesentery; Metabolism; Methods; Microscope; Modeling; NG-Nitroarginine Methyl Ester; Names; Neprilysin; Nifedipine; Nitric Oxide Synthase; Outcome; Pap smear; Pathway interactions; Peptide Fragments; Pharmaceutical Preparations; Phenylephrine; Phorbol; Phorbols; Postmenopause; Premenopause; Preparation; Production; Protein Kinase C; RBM5 gene; Rattus; Receptor Gene; Regulation; Relaxation; Renin; Renin-Angiotensin System; Resistance; Rho-associated kinase; Role; Ryanodine Receptor Calcium Release Channel; Saphenous Vein; Sarcoplasmic Reticulum; Sex Characteristics; Signal Pathway; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Sodium; Sodium Chloride; Solutions; Speed; Staining method; Stains; Staurosporine; System; Systolic Pressure; Testing; Time; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Weight; Western Blotting; Woman; analog; antagonist G; attenuation; clinically relevant; congenic; constriction; cyclopiazonic acid; extracellular; hormone therapy; immunocytochemistry; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; male; normotensive; pressure; protein expression; receptor; receptor binding; receptor downregulation; receptor expression; receptor internalization; release of sequestered calcium ion into cytoplasm; renal artery; research study; response; salt sensitive; vasoconstriction

Premenopausal females tiave a lower incidence of many cardiovascular diseases, including iiypertension. Because this protection steeply declines after menopause, we know that estrogen is at least partially responsible for these beneficial effects. There are two known estrogen receptor subtypes that mediate the genomic actions of this hormone; however, it is not known whether the newly discovered G protein-coupled receptor 30 (GPR30) contributes to estrogen's cardiovascular effects. Using the mRen2.Lewis rat, a unique angiotensin ll-dependent, estrogen-sensitive, and salt-sensitive hypertensive model which appropriately reflects the higher blood pressure and salt-sensitivity seen in postmenopausal women, we showed that in vivo administration of the selective GPR30 agonist G-1 in ovariectomized females significantly reduces blood pressure, alters vascular gene expression of renin-angiotensin system components, and reduces angiotensin ll-induced vasoconstriction. We hypothesize that GPR30 exerts beneficial cardiovascular effects by opposing the actions of Ang II in vascular smooth muscle cells. Separating the actions of estrogen at GPR30 from those mediated by its nuclear estrogen receptors may elucidate the current controversy surrounding hormone replacement therapy. The proposal will take a comprehensive approach utilizing an in vitro cell culture system, an ex vivo isolated resistance vessel preparation, and in vivo analysis ofthe congenic mRen2.Lewis hypertensive animal to determine (1) whether GPR30 activation in mesenteric smooth muscle cells influences calcium mobilization; (2) whether gender and estrogen status regulates expression of GPR30 in the vasculature; (3) whether GPR30 influences the function of renin-angiotensin system components; and (4) whether a high salt diet alters vascular GPR30 expression and function. These studies will establish the regulation of'Vascular GPR30 expression and assess its acute and chronic interaction with the renin-angiotensin system.

绝经前的女性患包括高血压在内的许多心血管疾病的发病率较低。 由于这种保护作用在绝经后急剧下降，我们知道雌激素至少部分地 对这些有益的影响负责。有两种已知的雌激素受体亚型介导 这种激素的基因组作用;然而，目前尚不清楚新发现的G蛋白偶联是否 受体30（GPR 30）有助于雌激素的心血管效应。使用mRen2.Lewis大鼠， 血管紧张素II依赖性、雌激素敏感性和盐敏感性高血压模型， 反映了绝经后妇女的高血压和盐敏感性，我们发现， 选择性GPR 30激动剂G-1在卵巢切除雌性中的体内给药显著降低了 血压，改变血管基因表达的肾素-血管紧张素系统的组成部分，并减少 血管紧张素II诱导的血管收缩。我们假设GPR 30发挥有益的心血管作用， 通过对抗血管紧张素II在血管平滑肌细胞中的作用。分离雌激素的作用， GPR 30通过其核雌激素受体介导的表达可能阐明目前的争议。 激素替代疗法的影响 该提案将采取综合方法，利用体外细胞培养系统、离体分离的 阻力血管制备和同类mRen2.Lewis高血压动物的体内分析， 确定（1）肠系膜平滑肌细胞中的GPR 30活化是否影响钙动员; (2)性别和雌激素状态是否调节GPR 30在脉管系统中的表达;（3）是否 GPR 30影响肾素-血管紧张素系统成分的功能;（4）高盐饮食是否 改变血管GPR 30的表达和功能。这些研究将建立“血管”的调节机制， GPR 30表达，并评估其与肾素-血管紧张素系统的急性和慢性相互作用。