Endogenous Relaxin Regulates Vascular Function in Nonpregnant Females and Males

描述(由申请人提供)：虽然松弛素(RLX)传统上与妊娠期间生殖器官的功能有关，但它正在成为血管功能的重要参与者。我们先前的研究表明，循环中的RLX无论是在妊娠期间内源性释放，还是在清醒、未怀孕的雌性和雄性大鼠体内注射，都能诱导全身和肾脏血管扩张，并增加动脉顺应性。在这里，我们建议探索两个最重要的概念：(1)内源性RLX调节非妊娠女性和男性的血管功能，(2)存在一个局部的、血管衍生的RLX激素/受体系统。初步的分子分析表明，RLX和RLX受体在分离的啮齿动物动脉和培养的人类血管细胞中表达，功能研究表明，从缺乏M1松弛素基因的未怀孕雌性和雄性小鼠分离的动脉顺应性降低，肌源性反应性增强，这些概念得到了支持。我们设计了五个假设和具体目标来检验这两个支配性概念。在目标1和目标2中，我们建议通过进一步表征松弛素和松弛素受体在小鼠和人类血管组织中的表达来证实和扩展我们的初步研究。在目标3-5中，我们建议研究清醒和自由、长期使用仪器的野生型和RLX缺陷小鼠的稳定和脉动的全身动脉负荷和肾脏血流动力学，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介导非妊娠女性和男性的血管松弛和顺应性增加，以及局部的血管衍生RLX激素/受体系统的概念是新的。如果它们被证实，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相关的动脉收缩和僵硬增加(包括正常和加速)，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，而不是仅限于妊娠。

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.