Relaxin: The 'Elusive' Vasodilator of Pregnancy

描述(由申请人提供)：我们的目标是定义机制 负责母体对正常妊娠的循环适应。使用 表现出与妊娠相似的循环变化的妊娠大鼠模型 女性，我们发现内皮素通过内皮上的ETB受体亚型 介导一氧化氮(NO)依赖的肾血管扩张和高滤过 活体，以及降低体外小肾动脉的肌源性反应性。 我们进一步表明，妊娠激素松弛素(RLX)，血管扩张 通过ET/NO途径给非妊娠大鼠肾脏循环，并通过 用抗体中和内源性循环RLX，肾脏循环 对怀孕的适应被废除。根据这些发现，有四个 提出了一些假设来检验RLX在额外的心血管疾病中的作用 对怀孕的适应。假设1.心输出量和全球动脉 清醒大鼠的顺应性(AC)以及大、小鼠的顺应性 在体外，动脉在怀孕期间同时上升。假设2.心脏 清醒、完整或去卵巢大鼠的输出量和整体AC 体外大、小动脉顺应性同时升高 慢性给药重组人松弛素(RhRLX)，从而模仿 怀孕的情况。假设3.心输出量和全球AC的增加 在清醒的大鼠中怀孕，以及大剂量顺应性的增加 和体外的小动脉，被长期服用RLX所破坏 中和抗体或卵巢切除。假设4.与怀孕有关的问题 大动脉和小动脉顺应性的增加在没有 一个起作用的松弛蛋白基因。总而言之，我们建议RLX在两个方面都发挥作用 全身血管阻力的下降和全球AC的上升 怀孕，从而开始增加心输出量，同时保持 舒张压与维持心脏和心脏的有效偶联 动脉系统。我们进一步提出，血管重塑以及 动脉张力降低是全球AC升高的中介因素。这两个 众所周知的基质降解特性和新发现的肾血管扩张 RLX的特性使这种荷尔蒙成为导致这些 妊娠期间心血管的主要变化。我们的初步数据令人振奋 因为你对假设的支持。孕激素知识(S) 在这些显着的循环变化的基础上， 了解产妇对正常妊娠的适应情况，很可能 促进血管扩张反应是子痫前期的研究 不适当，并可能提供新的治疗方法(S)，以对抗血管老化和 非妊娠人群中的高血压。

DESCRIPTION (provided by applicant): Our goal is to define the mechanisms responsible for maternal circulatory adaptations to normal pregnancy. Using the gravid rat model which manifests circulatory changes comparable to pregnant women, we showed that endothelin via the ETB receptor subtype on endothelium mediates nitric oxide (NO)-dependent renal vasodilation and hyperfiltration in vivo, as well as reduced myogenic reactivity of small renal arteries in vitro. We further showed that the pregnancy hormone, relaxin (RLX), vasodilates the renal circulation via ET/NO when administered to nonpregnant rats, and by neutralizing endogenous circulating RLX with antibodies, the renal circulatory adaptations of pregnancy are abrogated. Based on these findings, four hypotheses are proposed which test the role of RLX in additional cardiovascular adaptations to pregnancy. Hypotheseis 1. Cardiac output and global arterial compliance (AC) in conscious rats, as well as the compliance of large and small arteries in vitro, rise concurrently during pregnancy. Hypothesis 2. Cardiac output and global AC in conscious, intact or ovariectomized rats, as well as the compliance of large and small arteries in vitro, rise concurrently during chronic administration of recombinant human relaxin (rhRLX), thereby mimicking the pregnant condition. Hypothesis 3. The rise in cardiac output and global AC of pregnancy in conscious rats, as well as the increase incompliance of large and small arteries in vitro, are abrogated by chronic administration of RLX neutralizing antibodies or by ovariectomy. Hypothesis 4. Pregnancy-related increases in large and small artery compliance are compromised in mice without a functioning relaxin gene. In summary, we suggest that RLX mediates both the decline in systemic vascular resistance and the rise in global AC during pregnancy, thereby initiating increases in cardiac output while maintaining diastolic pressure and preserving efficient coupling of the ventricular and arterial systems. We further propose that vascular remodeling as well as reduced arterial tone mediate the rise the rise in global AC. Both the well-know matrix-degrading properties and newly discovered renal vasodilatory attributes of RLX make this hormone a leading candidate responsible for these major cardiovascular changes in pregnancy. Our preliminary data are exciting because thy support the hypotheses. Knowledge of the pregnancy hormone(s) underlying these remarkable circulatory changes is crucial for complete understanding of maternal adaptation to normal pregnancy, will likely facilitate investigation of preeclampsia in which the vasodilatory response is inappropriate, and may provide new treatment(s) to combat vascular aging and hypertension in the nonpregnant population.