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 offsprin...