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

高龄非人类灵长类动物妊娠后代心血管疾病的发育起源

• 批准号: 10629732
• 负责人: Sarah N Cilvik
• 金额: $ 78.48万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629732
• 关键词: 14 year old; 8 year old; 9 year old; Address; Adult; Adult Children; Affect; Anatomy; Animal Model; Biological Markers; Biopsy; Birth; Blood; Blood Pressure; Blood Vessels; Blood flow; Blood specimen; Breeding; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Child; Chronic; Data; Developed Countries; Development; Diet; Disease model; EFRAC; Echocardiography; Elderly; Environment; Evaluation; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Functional disorder; Gestational Diabetes; Health; Histologic; Histology; Human; Hypertension; Image; Imaging Techniques; Impairment; Intervention; Ischemia; Knowledge; Life; Longitudinal Studies; Maternal Age; Measurement; Measures; Mediator; Modeling; Monkeys; Mothers; Outcome; Pathway interactions; Perfusion; Physiological; Physiology; Placenta; Placental Insufficiency; Placentation; Pre-Clinical Model; Pre-Eclampsia; Pregnancy; Public Health; Recovery; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Rodent; Sampling; Spontaneous abortion; Techniques; Testing; Time; Tissues; Ultrasonography; Umbilical Blood; Umbilicus; United States National Institutes of Health; Universities; Uterus; Woman; advanced maternal age; adverse outcome; adverse pregnancy outcome; age related; aged; biomarker evaluation; cardiac magnetic resonance imaging; cardiovascular risk factor; circulating biomarkers; clinically relevant; contrast enhanced; coronary fibrosis; early childhood; experience; extracellular; fetal; forest; heart function; intrauterine environment; male; medical schools; minimally invasive; multidisciplinary; negative affect; neonate; new therapeutic target; nonhuman primate; offspring; perinatal outcomes; pregnant; prevent; reproductive; reproductive senescence; reproductive success; response; serial imaging; stillbirth; therapeutic target; ultrasound; vervet; young adult

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.

项目概要 高龄产妇（≥35 岁；AMA）作为一个不可改变的因素，是一个稳步增长的公共卫生问题 不良妊娠结局的危险因素，如先兆子痫、死产和胎儿生长受限。 结果表明，宫内环境不利，这也可能使后代容易患上长期的疾病。 健康风险，例如心血管疾病。母亲年龄对宫内环境的影响。 仅在少数研究中对发展规划进行了调查，这些研究显示出轻微的影响 人类后代血压与母亲年龄呈正相关，有舒张压证据 成年雄性啮齿类动物（NHP）的功能障碍和缺血反应较差。 Vervet，代表了一种关键的临床前妊娠模型，与人类生殖密切相关 解剖学/生理学和胎儿发育，同时可以更好地控制混杂因素，例如饮食和 使用 NIH 支持的维克森林大学学院 Vervet 研究群 (VRC)。 医学以及我们多学科团队的互补专业知识，我们拥有独特的优势 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 通过结合成像以及血液和胎盘组织的重复采样来发现后代的疾病。 我们将： 1) 检验 NHP AMA 妊娠表现出母体心血管状况不佳的假设 使用系列超声心动图、血液检查以心脏舒张功能障碍的形式适应妊娠 AMA (11- 14 岁）和年轻产妇年龄（YMA，5-8 岁）2) 检验 NHP AMA 胎盘有证据的假设。 在整个怀孕期间使用系列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、胎儿生长评估和 整个怀孕期间胎盘活检的存活率和组织学评估 3) 检验成人的假设。 NHP AMA 妊娠的后代显示出舒张功能障碍和心肌纤维化增加的证据 使用当前 7 至 9 岁成年蛇和心脏磁共振与 YMA 后代进行比较 成像技术量化细胞外体积分数，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，并通过以下方式询问发育编程的可能机制 这些研究将是首批测量肾素-血管紧张素-醛固酮系统成分的研究。 研究 AMA 如何影响胎盘功能和心血管疾病的发育规划 了解临床相关的 NHP 模型。 AMA 妊娠的后代对于确定治疗目标和关键窗口期是必要的 可以预防或延缓心血管疾病发生的干预措施。