Mechanism of Vasopressin-Mediated Placental Vascular Resistance after Fetal Bypas

描述（由申请人提供）：先天性心脏病是所有出生缺陷中最常见的，每年出生的婴儿中有1 / 100。许多复杂的病变在胎儿早期就开始了，只是简单的缺陷，导致胎儿心脏内的血液流动模式异常，但最终导致主要心脏结构的异常发育。尽管新生儿心脏手术取得了巨大进步，但先天性心脏病患儿可能面临更高的发病率和显著的过早死亡风险。越来越多地，这些缺陷现在可以在妊娠早期（~20周）通过胎儿超声心动图识别，当产后结果严峻时，可以考虑在子宫内治疗。某些干预措施需要在子宫内进行心内直视手术，这反过来又需要体外循环支持。然而，胎儿旁路手术后的胎盘功能障碍仍然是胎儿心脏手术临床翻译的主要障碍。这种胎盘功能障碍表现为胎盘血管阻力增加，胎儿气体交换恶化，胎儿循环重新分配。尽管自20世纪80年代以来一直在努力，但胎儿旁路术导致胎盘血管阻力增加的机制仍未得到解释。作为我们将胎儿心脏手术转化为临床的长期目标的一部分，本研究的目的是证明胎儿应激激素抗利尿激素是胎儿心脏手术期间和术后胎儿循环功能障碍的关键介质和中心原因。应激激素抗利尿激素是胎儿/胎盘循环中的一种有效的血管收缩剂，主要通过其受体（V1和V2）增加胎盘血管阻力，这些受体存在于羊和人的胎盘组织中。胎儿损伤和胎儿心脏手术的高应激事件引起胎儿抗利尿激素水平迅速而深刻地增加（约为基线的100倍）。胎儿搭桥和心脏手术后的胎盘功能障碍具有血管加压素介导的血管收缩的所有典型特征：外周血管收缩增加，胎盘血管阻力，胎儿循环集中，如果不加以控制，将导致胎儿死亡。我们建议使用妊娠中期胎羊模型来检验抗利尿激素介导胎儿旁路后胎盘和胎儿血管循环紊乱的假设。特异性目的1验证了选择性V1抗利尿激素受体拮抗剂在胎儿心脏手术和旁路手术中防止胎盘血管阻力增加和改善胎儿气体交换的假设。特异性目的2定义胎盘中抗利尿激素受体作用的机制，该机制在胎儿心脏手术和胎儿旁路手术中引起胎盘血管阻力增加和胎盘功能障碍。确定胎盘抗利尿激素受体对胎儿旁路反应的机制将允许合理应用可用的抗利尿激素拮抗剂治疗。这种新颖的应用可以为胎儿外科医生提供一个合理的工具，将胎儿心脏手术的应用转化为临床或改善胎儿的预后。这一结果也可能转化为世界上第一次成功的人类胎儿开胸手术。公共卫生相关性：在美国每年出生的4万名患有心脏缺陷的婴儿中，有一些婴儿的缺陷非常复杂或危及生命，这些婴儿在子宫内进行矫正心脏直视手术将受益最多。然而，进行胎儿心内直视手术的能力取决于在手术期间提供体外循环支持而不会对胎盘造成伤害。使用标准的绵羊模型，我们的研究将检查在胎儿心脏直视手术中保护胎盘的药物的使用。通过这种方式，我们可以完善我们的技术，然后再尝试在人类婴儿身上进行这项手术。

DESCRIPTION (provided by applicant): Congenital heart disease is the most common of all birth defects, affecting 1 in 100 infants born each year. Many of the complex lesions begin early in fetal life as simple defects that cause abnormal blood flow patterns within the fetal heart, but ultimately result in abnormal development of major cardiac structures. Despite great advances in neonatal cardiac surgery, a child born with congenital heart disease will likely face far greater morbidity and significant risk of premature mortality. Increasingly, these defects can now be identified early in pregnancy (~20 weeks) by fetal echocardiography, allowing consideration of in utero therapy when postnatal outcomes are grim. Certain interventions require in utero open-heart surgery, which in turn necessitates cardiopulmonary bypass support. However, placental dysfunction following fetal bypass remains the primary impediment to clinical translation of fetal cardiac surgery. This placental dysfunction manifests as an increase in placental vascular resistance, deterioration in fetal gas exchange, and redistribution of fetal circulation. Despite continuing efforts since the 1980's, the mechanism(s) leading to increased placental vascular resistance with fetal bypass remain unexplained. As part of our long-term goal to translate fetal cardiac surgery to the clinic, the purpose of this study is to demonstrate that the fetal stress hormone vasopressin is a key mediator and central cause of fetal circulatory dysfunction during, and following fetal cardiac surgery. The stress hormone vasopressin is a potent vasoconstrictor in the fetal/placental circulation capable of increasing placental vascular resistance primarily through its receptors, (V1 & V2) which are present in ovine and human placental tissues. Fetal insults and the highly stressful event of fetal cardiac surgery elicit rapid and profound increases in fetal vasopressin levels, (~100 times baseline). Placental dysfunction following fetal bypass and cardiac surgery share all the classic hallmarks of vasopressin mediated vasoconstriction: increased peripheral vasoconstriction, placental vascular resistance, and centralized fetal circulation, which when uncontrolled, leads to fetal demise. We propose to test the hypothesis that vasopressin mediates the placental and fetal vascular circulatory disturbances seen following fetal bypass using a mid-gestation fetal sheep model. Specific Aim 1 tests the hypothesis that selective V1 vasopressin receptor antagonism prevents increased placental vascular resistance and improves fetal gas exchange with fetal cardiac surgery and bypass. Specific Aim 2 defines the mechanism(s) of vasopressin receptor actions in the placenta that cause increased placental vascular resistance and placental dysfunction with fetal cardiac surgery and fetal bypass. Defining the mechanism by which placental vasopressin receptors respond to fetal bypass will permit reasonable application of available vasopressin antagonist therapy. This novel application may provide the fetal surgeon with a reasonable tool to translate application of fetal cardiac surgery to the clinic or improve fetal outcomes. The results could also translate into the world's first successful human fetal open-heart procedure. PUBLIC HEALTH RELEVANCE: Some of the 40,000 babies born every year in the United States with heart defects have defects so complex or life-threatening that these babies would benefit most from corrective open heart surgery performed when they are still in the womb. However, the ability to perform fetal open-heart surgery depends on providing cardiopulmonary bypass support during surgery without causing harm to the placenta. Using a standard sheep model our study will examine the use of medications that would protect the placenta during fetal open heart surgery. In this way we can perfect our techniques before attempting this procedure in human babies.