Developmental Origins of Cardiovascular Disease in Offspring from Non-Human Primate Pregnancies at Advanced Maternal Age

项目摘要 高龄产妇（≥35岁; AMA）是一个稳步增长的公共卫生问题， 不良妊娠结局的风险因素，如先兆子痫、死产和胎儿生长受限。这些 结果表明，不利的宫内环境，这也可能使后代长期 健康风险，如心血管疾病。母亲年龄对子宫内环境的影响， 发展规划只在少数研究中进行了研究，这些研究显示出轻微的 人类后代血压与母亲年龄之间呈正相关，有舒张压升高的证据 功能障碍和对局部缺血的不良反应。非人类灵长类动物（NHP），如 vervet是一种重要的临床前妊娠模型， 解剖学/生理学和胎儿发育，同时允许更好地控制混杂因素，如饮食和 环境利用美国国立卫生研究院（NIH）支持的维克森林维克森林大学医学院的马鞭草研究群（VRC）， 医学，以及我们的多学科团队的互补专业知识，我们是独一无二的准备， 纵向评估母亲年龄对NHP妊娠生理和慢性心血管疾病的影响 通过对血液和胎盘组织进行成像和重复采样， 我们将：1）检验NHP AMA妊娠表现出母体心血管不良的假设 心脏舒张功能不全的妊娠适应性变化，采用连续超声心动图，血液 压力测量和母体血液生物标志物分析在整个怀孕期间在美国医学会（11- 14岁）和年轻母亲年龄（YMA，5- 8岁）。2)检验NHP AMA胎盘有证据表明 整个怀孕期间使用连续对比增强超声成像减少微血管灌注， 除了子宫/脐血流的标准多普勒测量外， 存活率和整个妊娠期间胎盘活检的组织学评价。3)验证成年人 NHP AMA妊娠的后代显示舒张功能障碍和心肌纤维化增加的证据 与YMA后代相比，使用目前7至9岁的成年黑尾鹿和心脏磁共振 成像技术来量化细胞外容积分数，这是心肌纤维化的非侵入性测量。 此外，我们将使用超声心动图来量化舒张功能，测量循环生物标志物， 心脏应变和重塑，并询问发育编程的可能机制， 测量血管紧张素-醛固酮系统的成分。这些研究将是第一批 研究AMA如何影响胎盘功能和心血管疾病的发育程序， 临床相关NHP模型。了解发生在母亲和母亲身上的病理生理变化， 从AMA妊娠的后代是必要的，以确定治疗目标和关键窗口， 可以预防或延迟心血管疾病发作的干预措施。

Project Summary Advanced maternal age (≥35 years; AMA) is a steadily increasing public health concern as a non-modifiable risk factor for adverse pregnancy outcomes such as pre-eclampsia, stillbirth, and fetal growth restriction. These outcomes indicate an unfavorable intrauterine environment, which can also predispose offspring to long-term health risks such as cardiovascular disease. The effects of maternal age on the intrauterine environment and developmental programming have only been investigated in a handful of studies, which have shown a slight positive correlation between offspring blood pressure and maternal age in humans, with evidence of diastolic dysfunction and poor response to ischemia in adult male rodents. Non-human primates (NHP), such as the vervet, represent a critical preclinical model of pregnancy that closely mirrors human reproductive anatomy/physiology and fetal development, while allowing for better control over confounders, such as diet and environment. Using the NIH-supported Vervet Research Colony (VRC) at Wake Forest University School of Medicine, as well as the complementary expertise of our multidisciplinary team, we are uniquely poised to longitudinally assess the effects of maternal age on NHP pregnancy physiology and chronic cardiovascular disease in offspring, through a combination of imaging and repeated sampling of blood and placental tissue. We will: 1) Test the hypothesis that NHP AMA pregnancies demonstrate poor maternal cardiovascular adaptation to pregnancy in the form of cardiac diastolic dysfunction using serial echocardiography, blood pressure measurement, and maternal blood biomarker analysis throughout pregnancy in vervets at AMA (11- 14y) and young maternal age (YMA, 5-8y). 2) Test the hypothesis that NHP AMA placentas have evidence of decreased microvascular perfusion using serial contrast-enhanced ultrasound imaging throughout pregnancy, in addition to standard Doppler measurements of uterine/umbilical flow, assessment of fetal growth and survival, and histologic evaluation of placental biopsies throughout pregnancy. 3) Test the hypothesis that adult offspring from NHP AMA pregnancies show evidence of diastolic dysfunction and increased myocardial fibrosis compared to YMA offspring using current 7- to 9-year-old adult vervets and cardiac magnetic resonance imaging techniques to quantify the extracellular volume fraction, a non-invasive measure of myocardial fibrosis. Additionally, we will use echocardiography to quantify diastolic function, measure circulating biomarkers of cardiac strain and remodeling, and interrogate a possible mechanism for developmental programming by measuring components of the renin-angiotensin-aldosterone system. These studies will be among the first to investigate how AMA affects placental function and developmental programming of cardiovascular disease in a clinically relevant NHP model. Understanding the pathophysiological changes that occur in both mothers and offspring from AMA pregnancies is necessary to identify therapeutic targets and critical windows for intervention that can prevent or delay the onset of cardiovascular disease.