Role of Endothelin B Receptor in Vascular Protection in Females

内皮素B受体在女性血管保护中的作用

• 批准号: 7990293
• 负责人: Raouf A Khalil
• 金额: $ 21.78万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990293
• 关键词: Affect; Age; Agonist; Animals; Aorta; Biological Assay; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Chronic; Cyclic AMP; Cyclic GMP; Data; Dose; Down-Regulation; Endothelial Cells; Endothelin; Endothelin B Receptor; Endothelin-1; Endothelium; Enzymes; Estrogens; Excretory function; Female; Fluorescence; Fura-2; Hypertension; Image; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Infusion procedures; Kidney; Light; Link; Measures; Mediating; Menopause; Mesenteric Arteries; Mesentery; Messenger RNA; Microscopy; Molecular; Muscle Contraction; Nitric Oxide; Ovariectomy; Pathway interactions; Play; Postmenopause; Premenopause; Prevalence; Production; Prostaglandins I; Protein Kinase C; Proteins; Radioimmunoassay; Rattus; Regulation; Relaxation; Reverse Transcriptase Polymerase Chain Reaction; Rho-associated kinase; Role; Sex Characteristics; Small Interfering RNA; Smooth Muscle; Smooth Muscle Myocytes; Sprague-Dawley Rats; Testing; Tissues; Transgenic Organisms; Up-Regulation; Vascular Endothelium; Vascular Endothelium-Dependent Relaxation; Vascular Smooth Muscle; Vascular resistance; Vasodilator Agents; Western Blotting; Woman; base; citrate carrier; in vivo; male; men; protective effect; public health relevance; receptor expression; receptor upregulation; renal artery; research study; urinary; vasoconstriction

DESCRIPTION (provided by applicant): Cardiovascular disease is less common in premenopausal women compared with men of the same age, but dramatically increases in postmenopausal women. Also, experimental data have suggested protective effects of estrogen (E2) on the vascular endothelium by affecting the release of vasodilator factors such as nitric oxide and vasoconstrictive factors such as endothelin-1 (ET-1). ET-1 activates both endothelin A (ETAR) and endothelin B receptors (ETBR). Although the role of ETAR in mediating vasoconstriction and hypertension (HTN) has been studied extensively, the role of ETBR in the regulation of vascular function and blood pressure (BP) particularly in females is not clearly defined. The objective of this proposal is to test the hypothesis that the endothelial ETBR plays a major role in the regulation of vascular function in females. An increase in the expression/activity of ETBR activates endothelium-dependent vascular relaxation pathways, and counteracts the ET- 1/ETAR-mediated vasoconstriction, and thereby provides a vascular protective mechanism against HTN in females. E2-deficient states are associated with decreased endothelial ETBR expression/activity, unbalanced increase in ETAR-mediated vasoconstriction and HTN. Therefore, upregulation of ETBR activity enhances the benefits of E2 replacement on BP and vascular function in E2-deficient females. To test this hypothesis experiments will be conducted on intact males, as well as intact, ovariectomized (OVX) female, and E2-replaced OVX female Sprague-Dawley rats. The specific aims are to determine: 1) Whether the decreased BP in females reflects an upregulation of endothelial ETBR expression/activity and activation of ETBR-mediated nitric oxide (NO)-cGMP, prostacyclin (PGI2)-cAMP and hyperpolarizing factor (EDHF) vascular relaxation pathways. 2) Whether E2 deficiency in females is associated with increased BP due to downregulation of ETBR expression/activity, and unbalanced activation of ETAR-mediated [Ca2+]I, protein kinase C (PKC) and Rho-kinase pathways of vascular smooth muscle (VSM) contraction. 3) Whether upregulation of ETBR activity enhances the beneficial effects of E2 replacement on BP and vascular function in E2- deficient females. The results from these exploratory studies should help to define better the ETBR- mediated vascular protective mechanisms in females. The studies will also shed light on the potential benefits of ETBR upregulation as a complementary approach to enhance the vascular benefits of E2 replacement on the vasoconstriction and HTN associated with E2 deficiency in menopausal women. PUBLIC HEALTH RELEVANCE: Sex differences in the prevalence of cardiovascular disease have been suggested. The objective of this proposal is to investigate whether the endothelin B receptor subtype in the vascular endothelium plays a major role in the sex differences in vascular function, and in protecting against hypertension in females. These studies should help to understand better the vascular protective mechanisms of endothelin B receptors in females, and would shed light on the pathophysiological basis of the increased vascular resistance and hypertension associated with estrogen deficiency in menopausal women.

描述（由申请人提供）：与年龄相同的男性相比，心血管疾病在绝经前女性中不太常见，但绝经后妇女的增加。同样，实验数据表明，雌激素（E2）通过影响血管舒张因子的释放（例如一氧化氮和血管收缩因子，例如内皮素-1（ET-1））的释放来表明雌激素（E2）对血管内皮的保护作用。 ET-1激活内皮素A（ETAR）和内皮素B受体（ETBR）。尽管已经对ETAR在介导血管收缩和高血压（HTN）中的作用进行了广泛的研究，但ETBR在血管功能和血压调节（BP）调节中的作用尚未明确定义。该提议的目的是检验以下假设：内皮ETBR在女性血管功能的调节中起主要作用。 ETBR的表达/活性的增加激活了依赖内皮的血管弛豫途径，并抵消ET-1/ETAR介导的血管收缩，从而提供了针对女性HTN的血管保护机制。 E2缺陷状态与内皮ETBR表达/活性降低，ETAR介导的血管收缩和HTN不平衡有关。因此，ETBR活性的上调提高了E2缺陷女性中E2替代对BP和血管功能的益处。为了测试这一假设实验，将对完整的男性以及完整的卵巢切除（OVX）女性和E2重取的OVX雌性Sprague-Dawley大鼠进行。具体目的是确定：1​​）女性的BP降低是否反映了内皮ETBR表达/活性的上调，以及ETBR介导的一氧化氮（NO）-CGMP，前列环蛋白（PGI2） - 训练蛋白（PGI2）-CAMP和超极化因子（EDHF）血管弛豫途径的激活。 2）女性的E2缺乏是否与ETBR表达/活性下调以及ETAR介导的[Ca2+] I，蛋白激酶C（PKC）和血管平滑肌（VSM）血管平滑肌（VSM）的Rho-kinase途径的不平衡激活是否与BP增加有关。 3）ETBR活性的上调是否增强了E2替代对E2缺陷女性BP和血管功能的有益作用。这些探索性研究的结果应有助于更好地定义女性中介导的血管保护机制。这些研究还将揭示ETBR上调的潜在益处，作为一种补充方法，以增强E2替代的血管益处，并在更年期妇女的E2缺乏症中对血管收缩和HTN的血管益处。 公共卫生相关性：已经提出了心血管疾病患病率的性别差异。该提案的目的是研究血管内皮中的内皮素B受体亚型是否在血管功能的性别差异中起主要作用，并保护女性的高血压。这些研究应有助于更好地理解女性内皮素B受体的血管保护机制，并阐明与绝经女性雌激素缺乏相关的血管抵抗和高血压的病理生理基础。