Endogenous Relaxin Regulates Vascular Function in Nonpregnant Females and Males

描述（由申请人提供）：尽管传统上与妊娠期间生殖器官的功能相关，但松弛素（Rlx）正在成为血管功能的重要参与者。我们以前表明，循环Rlx无论是内源性释放在怀孕期间或外源性管理有意识的，非怀孕的女性和男性大鼠诱导全身和肾脏血管舒张，并增加动脉顺应性。在这里，我们建议探讨两个总体概念：（1）内源性Rlx调节非妊娠女性和男性的血管功能，和（2）有一个本地的，血管衍生的Rlx激素/受体系统。这些概念得到初步分子分析的支持，显示Rlx和Rlx受体表达的啮齿动物动脉和培养的人血管细胞，以及功能研究表明减少的顺应性和增加的肌原性反应性的动脉分离的非妊娠的女性和男性小鼠缺乏M1松弛素基因。我们设计了五个假设和具体目标来测试这两个总体概念。在目标1和2中，我们建议通过进一步表征小鼠和人血管组织中松弛素和松弛素受体的表达来证实和扩展我们的初步研究。在目标3-5中，我们提出研究清醒和不受限制的、长期仪器化野生型和Rlx缺陷小鼠中的稳定和脉动全身动脉负荷和肾血流动力学，以及从这些动物分离的动脉的肌源性反应性和被动力学。这些研究将利用未怀孕的雌性和雄性小鼠，以及年轻和年长的动物，从而探索性别和年龄的相互作用。据我们所知，内源性Rlx介导的血管舒张和增加非妊娠女性和男性的依从性，以及局部的血管源性Rlx激素/受体系统的概念是新颖的。如果它们得到验证，那么内源性Rlx或其受体的异常可能导致各种血管病理，例如，缺乏可能导致与高血压和衰老（正常和加速）相关的动脉收缩和僵硬增加，而过量可能导致主动脉瘤形成和夹层。因此，内源性Rlx对血管功能的影响可能是一种普遍现象，而不仅仅限于妊娠。

DESCRIPTION (provided by applicant): Although traditionally associated with function of reproductive organs during pregnancy, relaxin (Rlx) is emerging as an important player in vascular function. We previously showed that circulating Rlx whether endogenously released during pregnancy or exogenously adminstered to conscious, nonpregnant female and male rats induces systemic and renal vasodilation, and increases arterial compliance. Here, we propose to explore two overarching concepts: (1) endogenous Rlx regulates vascular function in nonpregnant females and males, and (2) there is a local, vascular-derived Rlx hormone/receptor system. These concepts are supported by preliminary molecular analyses showing Rlx and Rlx receptor expression by isolated rodent arteries and cultured human vascular cells, as well as by functional studies demonstrating reduced compliance and increased myogenic reactivity of arteries isolated from nonpregnant female and male mice deficient in the M1 relaxin gene. We have designed five Hypotheses and Specific Aims to test these two overarching concepts. In Aims 1 and 2, we propose to corroborate and extend our preliminary studies by further characterizing the expression of relaxins and relaxin receptors in vascular tissues from mice and humans. In Aims 3-5, we propose to investigate steady and pulsatile systemic arterial loads, and renal hemodynamics in conscious and unrestrained, chronically instrumented wild-type and Rlx-deficient mice, as well as myogenic reactivity and passive mechanics of arteries isolated from these animals. These studies will utilize nonpregnant female and male mice, as well as both young and older animals, thereby exploring gender and age interactions. To our knowledge, the concepts of endogenous Rlx mediating vascular relaxation and increased compliance in nonpregnant females and males, and of a local, vascular-derived Rlx hormone/receptor system are novel. If they are validated, then abnormalities in endogenous Rlx or its receptor may contribute to various vascular pathologies, e.g., a deficiency might contribute to increased arterial constriction and stiffness associated with hypertension and aging (both normal and accelerated), and an excess might contribute to aortic aneurysm formation and dissection. Thus, the influence of endogenous Rlx on vascular function is likely to be a general phenomenon, and not one limited exclusively to pregnancy.