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

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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.