Mechanisms of Renal Vasodilation by Relaxin

描述（由申请人提供）：卵巢激素松弛素是正常妊娠期间引起肾脏和全身血管深度舒张以及母体循环动脉顺应性增加的重要信号。这些变化对于启动和适应母体血容量和流量的增加是重要的，这反过来又支持胎儿生长。当妊娠期循环松弛素缺乏时，肾脏和全身动脉适应性受损。鉴于其在正常妊娠动脉变化中的突出作用，了解松弛素在脉管系统中的作用机制是很重要的。这种理解有可能解释在胎儿生长经常受到损害的子痫前期血管舒张和动脉顺应性的失调。最终，松弛素的血管舒张作用依赖于内皮一氧化氮，一氧化氮使血管平滑肌松弛。这项拨款提案的主要假设是松弛素的血管扩张作用取决于血管平滑肌和内皮之间的双向通讯。初步数据表明，松弛素主要受体Lgr7介导了松弛素的肾血管舒张性和动脉顺应性变化。然而，令人惊讶的是，进一步的初步结果显示血管平滑肌中的Lgr7受体明显多于内皮。因此，第一个假说和Specific Aim探讨了是否是血管平滑肌中的Lgr7受体介导了舒张素的肾血管舒张性和动脉顺应性变化。生成条件敲除血管平滑肌Lgr7的小鼠，以检测松弛素在这些小鼠中的肾血管舒张性和动脉顺应性改变是否被消除。第二个假说和特定目的是研究由松弛素刺激的血管平滑肌中的分子中间体，这些分子中间体反过来与内皮细胞进行交流。在这方面，新的和令人兴奋的初步数据涉及血管内皮生长因子。同样，第二个假说和特异性目的涉及内皮细胞中受刺激导致NO活性增加的分子中间体。这些假设和特定目的将通过研究分别从小鼠和人类分离的肾小动脉和皮下动脉的功能，以及有意识小鼠的肾血流量和动脉压来质疑。这个项目非常适合R21资助机制，因为它是探索性的，测试了松弛素在肾循环中的作用的新机制模型，提出了一种新的方法来测试体内需要开发的机制模型（靶向基因敲除小鼠），最后，但并非最不重要的是，将促进松弛素（或松弛素模拟物）作为血管扩张剂和动脉顺应性调节剂的治疗应用。事实上，松弛素在正常妊娠期心血管适应中的根本重要性，为在妊娠期病理生理心血管失调条件下对松弛素信号的药理学操纵的有效性提供了希望。公共卫生相关性：卵巢分泌的一种叫做松弛素的激素是一种关键信号，它作用于血管，在正常妊娠期间增加母体血流量，这对支持胎儿生长很重要。我们打算找出松弛素是如何影响血管导致这种变化的。了解松弛素在血管中的作用机制很重要，主要有两个原因：(i)它将有助于我们了解异常妊娠，如先兆子痫，其中主要问题是母体血流量减少；（ii）有必要将松弛素作为一种治疗剂用于治疗妊娠和非妊娠人群的各种血管疾病。

DESCRIPTION (provided by applicant): The ovarian hormone, relaxin, is an important signal causing profound renal and systemic vasodilation, as well as increased arterial compliance in the maternal circulation during normal pregnancy. These changes are important for both initiating and accommodating increased maternal blood volume and flow that, in turn, support fetal growth. When circulating relaxin is deficient in pregnancy, renal and systemic arterial adaptations are compromised. Given its prominent role in the arterial changes of normal pregnancy, it is important to understand the mechanisms of relaxin action in the vasculature. Such understanding has the potential to explain dysregulation of vasodilation and arterial compliance during preeclampsia in which fetal growth is frequently compromised. Ultimately, vasodilation by relaxin depends on endothelial nitric oxide that relaxes the underlying vascular smooth muscle. The overarching hypothesis of this grant proposal is that the vasodilatory actions of relaxin hinge on bi-directional communication between the vascular smooth muscle and the endothelium. Preliminary data indicate that the major relaxin receptor, Lgr7, mediates the renal vasodilatory and arterial compliances changes of relaxin. Surprisingly, however, further preliminary results show substantially more Lgr7 receptor in vascular smooth muscle than endothelium. Thus, the first Hypothesis and Specific Aim address whether it is the Lgr7 receptor in the vascular smooth muscle that mediates the renal vasodilatory and arterial compliances changes of relaxin. Mice with conditional knock-out of the Lgr7 from the vascular smooth muscle will be generated, in order to test whether the renal vasodilatory and arterial compliance changes of relaxin are abolished in these mice. The second Hypothesis and Specific Aim address the molecular intermediate(s) stimulated by relaxin in the vascular smooth muscle that, in turn, communicate with the endothelium. In this respect, new and exciting preliminary data implicate vascular endothelial growth factor. As well, the second Hypothesis and Specific Aim address the molecular intermediate(s) stimulated in the endothelium leading to increased NO activity. These Hypotheses and Specific Aims will be interrogated by studying the function of small renal and subcutaneous arteries isolated from mice and humans, respectively, as well as renal blood flow and arterial pressure in conscious mice. This project is ideally suited to the R21 funding mechanism because it is exploratory, testing a novel mechanistic model of relaxin action in the renal circulation, proposes a new methodological approach to testing this mechanistic model in vivo that is in need of development (targeted gene knock-out mice), and last, but not least, will facilitate the therapeutic application of relaxin (or relaxin mimetic) as a vasodilator and modifier of arterial compliance. Indeed, the fundamental importance of relaxin in the cardiovascular adaptations of normal pregnancy holds promise for the effectiveness of pharmacologic manipulation of relaxin signaling in conditions of pathophysiological cardiovascular dysregulation in pregnancy. PUBLIC HEALTH RELEVANCE: A hormone from the ovary called relaxin is a key signal that acts on blood vessels to increase maternal blood flow during normal pregnancy that is important to support fetal growth. We propose to find out how relaxin affects blood vessels to cause this change. It is important to understand the mechanisms of action of relaxin in blood vessels for two main reasons: (i) it will help us understand abnormal pregnancy such as preeclampsia in which the major problem is decreased maternal blood flow, and (ii) it is necessary for potential use of relaxin as a therapeutic agent to treat various blood vessel diseases in the pregnant and nonpregnant populations.