BME PhD Prospectus Presentation: Madison Fletcher

Title: "A spiral artery remodeling chip-based platform for preeclampsia-targeted drug screening"

Advisory Committee: N/A

Abstract: Spiral arteries serve as the main blood supply to endometrial tissue in the uterus, which develop in concert with the rapid growth and differentiation of stromal endometrial tissue into a specialized, decidual state to prepare for embryo implantation and pregnancy. An integral act of placental development occurs as spiral arteries within the decidua are morphologically and functionally transformed by invading fetal cells. This process, known as spiral artery remodeling (SAR), is critical as it allows for increased oxygen and nutrients to reach the fetus as it grows. A dysregulated decidual microenvironment and minimal remodeling has been identified in severe growth-restrictive pregnancy-related conditions, like preeclampsia (PE). Although PE is understood as the onset of hypertension and proteinuria after 20 weeks of gestation, a mechanistic root of development and understanding of how SAR is inhibited has yet to be determined—limiting the development of effective and targeted drugs for severe patients. Thus, to improve our understanding of SAR and PE for future therapeutic development, there remains a need for a laboratory model system that can functionally mimic human endometrial spiral arteries and allow for microenvironmental control. Microfluidic in vitro models are a promising tool for human microenvironmental and tissue mimicry due to their geometric complexity, modular nature, and importantly, their compatibility with human-derived cells. As these models provide significant advantages over physiologically inaccurate small animal models, their use in effective drug screening should be explored. Our novel in vitro multi-well vasculature-on-a-chip platform of perfusable endometrial vasculature has provided insights into factors that affect vascular functional and structural development, as well as allowed us to visualize the effects of fetal cell-mediated vascular remodeling in real-time. However, our use of non-endometrial (lung) stromal cells within the vascular system limits the physiological relevance and utility of our model. Thus, I propose to increase the physiological relevance of our model by utilizing human decidual stromal cells to 1) develop perfusable decidual-specific vasculature within a SAR-specific fibrin-based hydrogel perivascular matrix. Then, I aim to use this platform to 2) mimic and further investigate SAR within non-diseased and preeclamptic decidual microenvironments. Finally, in effort to progress targetable PE therapeutic development and translation, I aim to 3) identify potential repurposed drug candidates that prevent SAR inhibition through screening of small molecule-based FDA-approved drugs within the pathophysiological vascular model.