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；美国医学会)代表着一个稳步增长的公共卫生问题，作为非 不良妊娠结局的可改变危险因素，如先兆子痫、死产和胎儿生长 限制。这些结果表明不利的宫内环境，这也可能是易患 子女面临长期的健康风险，如心血管疾病。产妇年龄对母体发育的影响 宫内环境和发育规划只在少数几项研究中进行了调查， 在人类中，孩子的血压和母亲的年龄之间显示出轻微的正相关， 有证据表明成年雄性啮齿动物存在舒张期功能障碍和对缺血的不良反应。非人 灵长类(NHP)，如鞭毛虫，代表了一种关键的临床前妊娠模式，与 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。在Wake使用NIH支持的VerveT研究群体(VRC) 森林医学院，我们独一无二地准备纵向评估产妇年龄对NHP的影响 子代的妊娠生理学和慢性心血管疾病 反复采集血液和胎盘组织。我们的具体目标是：1)检验NHP AMA的假设 妊娠表现出孕妇心血管对妊娠的不良适应，心脏舒张期 系列超声心动图、血压测量和母体血液生物标志物对功能障碍的影响 AMA(11-14岁；N=16)和年轻母亲年龄(YMA；5-8)的整个孕期分析 年龄；N=16)。2)检验NHP AMA胎盘微血管减少的假设 在整个妊娠期间使用连续对比增强超声(CEUS)成像进行灌流。此外，我们 将获得子宫/脐带血流的标准多普勒测量，通过超声波跟踪胎儿生长， 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妊娠的成年后代表现出舒张期功能障碍和 与YMA后代相比，使用目前8至10岁的成年马鞭草和 先进的心脏磁共振成像(CMRI)技术可以量化细胞外体积分数， 心肌纤维化的无创性测量(AMA男性N=4-6，AMA男性N=4-6，AMA女性N=6-8， YMA雌虫N=6-8)。此外，我们将使用超声心动图来量化和测量舒张期功能。 心脏应变和重塑的血液生物标志物。这些研究将是第一批研究如何 AMA影响心血管疾病胎盘功能和发育规划的临床研究 相关的NHP模型。对母体和母体的病理生理变化的理解 AMA妊娠的后代对于确定治疗靶点和关键窗口是必要的 可以预防或延缓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.