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.

绝经前女性许多心血管疾病的发病率较低，包括高血压。 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 负责这些有益的影响。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，尚不清楚新发现的G蛋白偶联是否 受体 30 (GPR30) 有助于雌激素的心血管作用。使用 mRen2.Lewis 大鼠，一种独特的 血管紧张素II依赖型、雌激素敏感型和盐敏感型高血压模型 反映了绝经后妇女的较高血压和盐敏感性，我们表明 选择性 GPR30 激动剂 G-1 在卵巢切除女性体内的体内给药显着降低 血压，改变肾素-血管紧张素系统成分的血管基因表达，并降低 血管紧张素II诱导的血管收缩。我们假设 GPR30 发挥有益的心血管作用 通过对抗 Ang II 在血管平滑肌细胞中的作用。分离雌激素的作用 来自其核雌激素受体介导的 GPR30 可能会阐明当前的争议 周围激素替代疗法。 该提案将采取综合方法，利用体外细胞培养系统，离体分离 同系 mRen2.Lewis 高血压动物的阻力血管制备及体内分析 确定 (1) 肠系膜平滑肌细胞中 GPR30 的激活是否影响钙动员； (2)性别和雌激素状态是否调节脉管系统中GPR30的表达； (3) 是否 GPR30影响肾素-血管紧张素系统成分的功能； (4)是否高盐饮食 改变血管 GPR30 表达和功能。这些研究将建立“血管”的调节 GPR30 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。