Magnetic Resonance Imaging (MRI) is a powerful tool for the noninvasive, real-time visualization of biological structures and with refined approaches, the assessment of their associated functions and physiological and pathophysiological processes. While providing intriguing opportunities to probe placenta health across gestation, it is not routinely used in pregnant women due to fetal safety concerns. However, the powerful biological potential of these approaches can be applied to experimental animal models, and for the maternal- fetal interface, the nonhuman primate is the most compelling parallel to the human from a histological, endocrine and immunological perspective. We have optimized the sequences and determined the limitations for imaging the pregnant macaque uterus and maternal-fetal interface (MFI) in previous studies, and validated dynamic contrast enhancement (DCE) for assessing flow and perfusion in the placental intervillous space. In this grant we will apply our established MRI approaches to novel physiological stressors generating inflammation or dysfunction at the MFI and determine their feasibility as experimental tools in NHPs for assessing, in real time in vivo, perfusion, oxygenation, and progression to fetal growth restriction (FGR) in two Specific Aims.
Specific Aim 1. To utilize a physiological stimulator of macrophage trafficking, MCP1, to define the utility of MRI in detecting inflammation at the maternal-fetal interface and its potential to develop an NHP model of FGR.
Specific Aim 2. To use a hemostatic agent injected into the MFI to create vascular pathology, triggering inflammation and villous ischemic injury to define the utility of MRI to identify inflammation associated with vascular pathology at the MFI, and the potential for this insult to develop an NHP model of FGR. In these studies blood oxygen level dependent (BOLD) MRI will define tissue oxygenation and ferumoxytol DCE MRI will assess noninvasively changes in the populations of phagocytic cells retaining contrast agent at the MFI, to be associated with intervillous perfusion, oxygenation, histopathology, and cellular and molecular immune responses that we predict will ultimately manifest by the development of FGR in the macaque. At UW-Madison we have developed ferumoxytol imaging in the pregnant rhesus monkey to evaluate placental perfusion and translated this approach to the clinic in our current Human Placenta Project U01 grant with an approved IRB Human Subject study. Assessment of placental hypoperfusion lesions with DCE validated by confirmation of an adjacent villous hypo-oxygenated state and placental histopathology and immunopathology, will advance clinical care by dramatically improving the accuracy of diagnosis of FGR and enhancing our ability to identify fetuses at greatest risk for consequences of significant hypoxemia.
Maternal-fetal medicine clinicians still lack the ability to understand placental health and function, critical for a successful pregnancy, in real time with non-invasive methodologies. We propose to use experimental interventions in a nonhuman primate model expected to result in inflammation, placental and decidual lesions, and disrupted intervillous blood flow to refine and optimize magnetic resonance imaging as a method for the real-time assessment of placental function. Since inflammation and disrupted blood flow are thought to be primary contributors to adverse pregnancy outcomes including fetal growth restriction, these studies will work towards the ultimate goal to be able to identify problems and ?treat the placenta? to improve the health of both mothers and babies.