Mechanism of Vasopressin-Mediated Placental Vascular Resistance after Fetal Bypas

描述(申请人提供)：先天性心脏病是所有出生缺陷中最常见的，每年每100名新生儿中就有1人受到影响。许多复杂的损害开始于胎儿生命的早期，作为简单的缺陷，导致胎儿心脏内的异常血流模式，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很大进展，但出生时患有先天性心脏病的儿童可能面临更高的发病率和过早死亡的巨大风险。现在，这些缺陷越来越多地可以通过胎儿超声心动图在怀孕早期(~20周)识别出来，以便在出生后结局严峻的情况下考虑宫内治疗。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，胎儿搭桥术后的胎盘功能障碍仍然是胎儿心脏手术临床推广的主要障碍。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，胎儿循环重新分布。尽管自20世纪80年代S以来一直在努力，但(S)导致胎儿旁路胎盘血管阻力增加的机制仍不清楚。作为我们将胎儿心脏手术移植到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血管加压素是胎儿心脏手术期间和之后胎儿循环功能障碍的关键介质和中心原因。应激激素加压素是胎儿/胎盘循环中的一种强大的血管收缩因子，主要通过其受体(V1和V2)增加胎盘血管阻力，该受体存在于绵羊和人类胎盘组织中。胎儿的侮辱和胎儿心脏手术的高度应激事件导致胎儿加压素水平迅速和显著增加(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加压素介导的血管收缩的所有经典特征：外周血管收缩增加，胎盘血管阻力增加，胎儿集中循环，如果不加控制，会导致胎儿死亡。我们建议使用妊娠中期的胎羊模型来检验加压素介导胎儿搭桥术后胎盘和胎儿血管循环障碍的假说。具体目的1验证选择性V1血管加压素受体拮抗剂阻止胎盘血管阻力增加和改善胎儿心脏手术和体外循环胎儿气体交换的假设。特定目的2明确了胎盘中加压素受体作用的机制(S)，该机制导致胎盘血管阻力增加和胎儿心脏手术和胎儿转流中胎盘功能障碍。明确胎盘加压素受体对胎儿搭桥反应的机制将允许合理应用可用的加压素拮抗剂治疗。这一新的应用可能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结局。这一结果也可能转化为世界上第一个成功的人类胎儿心内直视手术。与公共卫生相关：美国每年出生的4万名患有心脏缺陷的婴儿中，有一些缺陷非常复杂或危及生命，这些婴儿将最大限度地受益于在他们还在子宫里的时候就进行的心脏矫形手术。然而，进行胎儿心脏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期间保护胎盘的药物的使用。通过这种方式，我们可以在尝试在人类婴儿身上进行这一过程之前完善我们的技术。

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.