Role of Endothelin B Receptor in Vascular Protection in Females

描述(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，但绝经后女性的心血管疾病显著增加。此外，实验数据表明，雌激素(E2)通过影响血管扩张因子(如一氧化氮)和血管收缩因子(如内皮素-1)的释放，对血管内皮细胞具有保护作用。ET-1可激活内皮素A(ETAR)和内皮素B受体(ETBR)。尽管ETAR在调节血管收缩和高血压(HTN)中的作用已被广泛研究，但ETBR在调节血管功能和血压(BP)中的作用尚不清楚，尤其是在女性。这一建议的目的是检验内皮ETBR在女性血管功能调节中发挥主要作用的假设。ETBR的表达/活性增加激活了内皮依赖的血管松弛通路，并抵消了ET-1/ETAR介导的血管收缩，从而为女性HTN提供了一种血管保护机制。E2缺乏状态与内皮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替代对缺乏E2的女性的血压和血管功能的好处。为了验证这一假设，实验将在完整的雄性，以及完整的，去卵巢(OVX)的雌性，以及替换了OVX的雌性SD大鼠身上进行。其具体目的是确定：1)女性血压下降是否反映了内皮ETBR表达/活性的上调和ETBR介导的一氧化氮(NO)-cGMP、前列环素(PGI2)-cAMP和超极化因子(EDHF)血管松弛途径的激活。2)雌二醇缺乏是否与ETBR表达/活性下调引起的血压升高有关，以及Etar介导的血管平滑肌收缩的[Ca~(2+)]i、蛋白激酶C(PKC)和Rho-Kinase途径的不平衡激活。3)ETBR活性上调是否增强了E_2替代对E_2缺乏女性血压和血管功能的有利影响。这些探索性研究的结果应该有助于更好地确定ETBR介导的女性血管保护机制。这些研究还将阐明ETBR上调作为补充方法的潜在好处，以增强E2替代对绝经期妇女血管收缩和HTN相关的血管收缩的益处。 公共卫生相关性：心血管疾病患病率的性别差异已被提出。本研究的目的是探讨血管内皮细胞内皮素B受体亚型是否在女性血管功能的性别差异以及预防高血压方面起主要作用。这些研究将有助于更好地了解女性内皮素B受体的血管保护机制，并有助于揭示绝经后女性雌激素缺乏导致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.