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，心血管疾病在绝经前女性中较少见，但在绝经后女性中显著增加。此外，实验数据表明，雌激素（E2）通过影响血管舒张因子（如一氧化氮）和血管收缩因子（如内皮素-1）的释放，对血管内皮具有保护作用。ET-1激活内皮素A （ETAR）和内皮素B受体（ETBR）。虽然ETAR在介导血管收缩和高血压（HTN）中的作用已被广泛研究，但ETBR在调节血管功能和血压（BP）（尤其是女性）中的作用尚未明确定义。本研究的目的是验证内皮细胞ETBR在女性血管功能调节中起主要作用的假设。ETBR表达/活性的增加激活内皮依赖性血管舒张通路，抵消ET- 1/ etar介导的血管收缩，从而为女性HTN提供血管保护机制。e2缺乏状态与内皮细胞ETBR表达/活性降低、etar介导的血管收缩和HTN的不平衡增加有关。因此，ETBR活性的上调增强了E2替代对E2缺乏女性血压和血管功能的益处。为了验证这一假设，实验将在完整的雄性大鼠，以及完整的卵巢切除（OVX）雌性大鼠和e2替代OVX雌性大鼠上进行。具体目的是确定：1)女性血压下降是否反映了内皮细胞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）血管舒张通路的激活。2) E2缺乏是否与血管平滑肌（VSM）收缩中ETBR表达/活性下调、etar介导的[Ca2+]I、蛋白激酶C （PKC）和rho激酶通路不平衡激活有关。3) ETBR活性的上调是否会增强E2替代对E2缺乏女性血压和血管功能的有益作用。这些探索性研究的结果将有助于更好地定义ETBR介导的女性血管保护机制。这些研究还将阐明ETBR上调作为一种补充方法的潜在益处，以增强E2替代对与E2缺乏相关的血管收缩和HTN的血管益处。

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.