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: 8661246
• 负责人: Sarah H. Lindsey
• 金额: $ 23.2万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661246
• 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.

绝经前女性患许多心血管疾病的几率较低，包括高血压。