Relaxin: The 'Elusive' Vasodilator of Pregnancy

描述（由申请人提供）：我们的目标是定义机制 负责母体循环系统对正常妊娠的适应。使用 妊娠大鼠模型，其表现出与妊娠大鼠相当的循环变化 我们发现，内皮素通过内皮细胞上的ETB受体亚型， 介导一氧化氮（NO）依赖性肾血管舒张和高滤过， 在体内，以及在体外降低小肾动脉的肌原性反应性。 我们进一步表明，妊娠激素松弛素（RLX）可以舒张血管， 通过ET/NO的肾循环，当给药于非妊娠大鼠时， 用抗体中和内源性循环RLX， 怀孕的适应性被废除。根据这些发现，四 提出了一些假设，这些假设检验了RLX在其他心血管疾病中的作用。 适应怀孕。假设1.心输出量和总动脉 顺应性（AC）在清醒的大鼠，以及顺应性的大小 动脉在体外，上升同时在怀孕期间。假设2.心脏 清醒、完整或卵巢切除大鼠的输出和整体AC，以及 体外大动脉和小动脉顺应性在 长期施用重组人松弛素（rhRLX），从而模拟 怀孕的条件。假设3.心输出量和总AC的增加 怀孕的清醒大鼠，以及增加不遵守大 和体外小动脉，被RLX的长期给药废除 中和抗体或卵巢切除术。假设4.妊娠相关 在小鼠中，大动脉和小动脉顺应性的增加受到损害， 松弛素基因总之，我们认为，RLX介导的两个 全身血管阻力下降和整体AC升高， 妊娠，从而启动心输出量增加，同时维持 舒张压，并保持心室和 动脉系统我们进一步提出，血管重塑以及 动脉张力降低介导了整体AC的升高。两者 众所周知的基质降解特性和新发现的肾血管舒张 RLX的属性使这种激素成为负责这些的主要候选人 怀孕期间的主要心血管变化。我们的初步数据令人振奋 因为你支持这些假设。妊娠激素的知识 这些显著的循环系统变化的基础是至关重要的 了解产妇对正常妊娠的适应情况， 促进先兆子痫的研究，其中血管舒张反应是 不合适，并可能提供新的治疗方法来对抗血管老化， 非妊娠人群的高血压。

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.