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（如先兆子痫、死产和胎儿生长）的可改变风险因素 限制.这些结果表明，不利的宫内环境，这也可能导致 这可能会导致后代长期健康风险，如心血管疾病。母亲年龄对妊娠结局的影响 子宫内环境和发育规划仅在少数研究中进行了研究， 这些研究表明，人类后代的血压与母亲的年龄之间存在轻微的正相关， 在成年雄性啮齿动物中有舒张功能障碍和对局部缺血反应差的证据。非人 灵长类动物（NHP），如长尾猴，代表了一种重要的临床前妊娠模型， 人类生殖解剖学/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。使用NIH支持的Vervet研究菌落（VRC）在唤醒 森林医学院，我们是唯一准备纵向评估产妇年龄对NHP的影响 妊娠生理学和慢性心血管疾病的后代，通过结合成像和 反复采集血液和胎盘组织样本我们的具体目标是：1）检验假设，NHP AMA 妊娠表现为母体心血管对妊娠的适应性差，表现为心脏舒张功能不全， 使用连续超声心动图、血压测量和母体血液生物标志物的功能障碍 在AMA（11-14岁; N=16）和年轻母亲年龄（YMA; 5-8岁）的黑尾长尾雉的整个妊娠期分析 年龄：N=16）。2)检验NHP AMA胎盘有微血管减少证据的假设 在整个妊娠期间使用连续对比增强超声（CEUS）成像进行灌注。另外我们 将获得子宫/脐血流的标准多普勒测量值，通过超声跟踪胎儿生长， 在整个妊娠期间进行胎盘活检以跟踪绒毛组织学，并量化胎儿死亡率。3)测试 假设NHP AMA妊娠的成年后代显示舒张功能障碍的证据， 与使用当前8至10岁成年黑尾长尾雉的YMA后代相比，心肌纤维化增加， 先进的心脏磁共振成像（cMRI）技术来量化细胞外容积分数， 心肌纤维化的非侵入性测量（AMA男性N=4-6，YMA男性N=4-6，AMA女性N=6-8， YMA女性N=6-8）。此外，我们将使用超声心动图来量化舒张功能， 心脏应变和重塑的血液生物标志物。这些研究将是第一批调查如何 AMA影响胎盘功能和心血管疾病的发育程序 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) represents 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 School of Medicine, 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. Our specific aims are: 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 (11-14 years old; N=16) and young maternal age (YMA; 5-8 years old; N=16). 2) Test the hypothesis that NHP AMA placentas have evidence of decreased microvascular perfusion using serial contrast-enhanced ultrasound (CEUS) imaging throughout pregnancy. In addition, we will acquire standard Doppler measurements of uterine/umbilical flow, follow fetal growth by ultrasound, perform placental biopsies to follow villus histology throughout pregnancy, and quantify fetal mortality. 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 8- to 10-year-old adult vervets and advanced cardiac magnetic resonance imaging (cMRI) techniques to quantify the extracellular volume fraction, a non-invasive measure of myocardial fibrosis (AMA males N=4-6, YMA males N=4-6, AMA females N=6-8, YMA females N=6-8). Additionally, we will use echocardiography to quantify diastolic function and measure blood biomarkers of cardiac strain and remodeling. 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 of 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.