Role of Endothelin B Receptor in Vascular Protection in Females

描述（由申请人提供）：与同龄男性相比，绝经前女性的心血管疾病较少见，但绝经后女性的心血管疾病显着增加。此外，实验数据表明，雌激素 (E2) 通过影响一氧化氮等血管舒张因子和内皮素-1 (ET-1) 等血管收缩因子的释放，对血管内皮发挥保护作用。 ET-1 激活内皮素 A (ETAR) 和内皮素 B 受体 (ETBR)。尽管 ETAR 在介导血管收缩和高血压 (HTN) 中的作用已得到广泛研究，但 ETBR 在调节血管功能和血压 (BP) 中的作用，特别是在女性中，尚不清楚。本提案的目的是检验内皮 ETBR 在女性血管功能调节中发挥重要作用的假设。 ETBR表达/活性的增加激活内皮依赖性血管舒张途径，并抵消ET-1/ETAR介导的血管收缩，从而提供针对女性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 不平衡增加有关。因此，ETBR 活性的上调增强了 E2 替代对缺乏 E2 的女性血压和血管功能的益处。为了验证这一假设，我们将在完整的雄性大鼠、完整的卵巢切除 (OVX) 雌性大鼠和 E2 替换 OVX 雌性 Sprague-Dawley 大鼠上进行实验。具体目的是确定：1​​) 女性血压下降是否反映了内皮 ETBR 表达/活性的上调以及 ETBR 介导的一氧化氮 (NO)-cGMP、前列环素 (PGI2)-cAMP 和超极化因子 (EDHF) 血管舒张途径的激活。 2) 女性 E2 缺乏是否与由于 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) 收缩的 Rho 激酶途径的不平衡激活而导致的血压升高有关。 3) ETBR 活性的上调是否会增强 E2 替代对缺乏 E2 的女性血压和血管功能的有益影响。这些探索性研究的结果应有助于更好地确定女性中 ETBR 介导的血管保护机制。这些研究还将阐明 ETBR 上调作为补充方法的潜在益处，以增强 E2 替代对更年期妇女与 E2 缺乏相关的血管收缩和高血压的血管益处。 公共卫生相关性：有人提出心血管疾病患病率存在​​性别差异。本提案的目的是调查血管内皮细胞中的内皮素 B 受体亚型是否在血管功能的性别差异以及预防女性高血压方面发挥重要作用。这些研究应有助于更好地了解女性内皮素B受体的血管保护机制，并揭示更年期女性与雌激素缺乏相关的血管阻力增加和高血压的病理生理学基础。

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.