There is a lack of reliable tools to assess the impact of promising treatments for preeclampsia on placental function and development; assessment of treatment efficacy is typically determined through measurements of maternal mean arterial pressure, which are not always correlated with fetal outcome. In the absence of such technology, the promise of an improved mechanistic understanding of preeclampsia pathophysiology ? necessary for the development of novel treatments to improve patient outcomes ? will likely remain unfulfilled. The long-term goal of this effort is to develop new functional imaging methods to improve the treatment of preeclampsia. The overall objective in this application is to establish new functional imaging methods to longitudinally measure in vivo placental perfusion, ischemia, and placental angiogenesis. Our central hypothesis is that fetal outcomes can be predicted by longitudinally monitoring placental perfusion, hypoxia, and angiogenesis using spectral photoacoustic (sPA) and targeted contrast enhanced ultrasound (CEUS) imaging. This hypothesis was formulated based on preliminary data from our lab and others establishing sPA imaging as a method to estimate longitudinal placental tissue oxygenation in vivo, and CEUS as a method to quantify in vivo tissue perfusion and angiogenesis. The rationale for the proposed research is that improved methods for longitudinal in vivo monitoring of preeclampsia will provide more accurate preclinical validation of potential treatments for preeclampsia. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) the development of methods to image in vivo placental oxygenation changes in response to therapy; and 2) the development of methods to image the longitudinal impact of therapies on placental growth. Under the first aim, spectral photoacoustic imaging will be implemented to estimate placental oxygenation during treatment; the imaging methods and the model of preeclampsia which will be used in this project, the reduced uterine perfusion pressure (RUPP) rat, have both been established as feasible in the applicants' hands. Under the second aim, contrast-enhanced ultrasound will be implemented to longitudinally track alterations in placental perfusion during preeclampsia treatment. Preliminary data in support of this objective demonstrates CEUS as a method of assessing placental perfusion and angiogenesis. This approach is innovative, because it represents a substantive departure from the status quo by shifting the research focus from maternal systemic dysfunction, to placental dysfunction, long recognized as the dominant underlying regulator in the development of preeclampsia. The establishment of multimodal in vivo imaging of placental function will constitute a significant improvement towards characterizing the physiological environment of the placenta during preeclampsia; acquiring this missing information is expected to open up new therapeutic options and move the field substantially towards improved treatment. This contribution is expected to have broad translational importance in the prevention and treatment of a range of pregnancy-associated diseases.
The proposed research is relevant to public health since the development of in vivo imaging tools to assess placental functional response will improve the treatment of preeclampsia. The proposed research is relevant to the part of the NIH's mission that pertains to research strategies to improve health, by reducing the maternal and fetal impacts of preeclampsia.
