BME PhD Dissertation: Sebastian Naranjo

Title: "THE DEVELOPMENT OF A FIRST-GENERATION SPIRAL ARTERY REMODELING MICROPHYSIOLOGICAL SYSTEM"

Advisory Committee: Joyce Wong, PhD – BME, MSE (Co-Advisor) Catherine Klapperich, PhD – BME, MSE, ME (Co-Advisor) Christopher Chen, MD,PhD – BME (Chair) Wendy Kuohung, MD - Obstetrics and Gynecology Michael Smith, PhD – BME

Abstract: Preeclampsia (PE) is the leading cause of maternal and fetal morbidity and mortality in the United States, accounting for more than 70,000 maternal and 500,000 fetal deaths annually. The predominant mechanistic hypothesis for its pathogenesis involves dysregulation of spiral artery remodeling (SAR)—a process in which invasive placental cells, known as extravillous trophoblasts (EVTs), remodel the maternal vasculature to meet the metabolic demands of the developing fetus during the 2nd and 3rd trimesters. Although considerable efforts have been made to develop a mechanistic understanding of PE, a clinically translatable comprehension of its mechanisms for disease presentation and treatment remains elusive. This challenge is largely due to the inability of current models to replicate the complex spatiotemporal microenvironmental intricacies required throughout the SAR process. To address this gap, a modular, endometrium-specific vascular model was developed utilizing primary human endometrial microvascular endothelial cells (HEMECs) within a low-absorption polystyrene (PS) organ-on-a-chip platform. This configuration enables the self-assembly of perfusable, spiral arteriole–scale vascular networks within a fibrin–collagen I matrix. Quantitative perturbations involving VEGF-A, bFGF, S1P, and menstrual cycle phase–specific estradiol/progesterone regimens demonstrate that hormonal and biochemical cues differentially influence endometrial vascular density, connectivity, permeability, and angiogenic secretomes. Introducing EVT cell lines into this vasculature reveals phenotype- and context-dependent endothelial remodeling. Overall, this study introduces a perfusable, endometrial-specific vascular new approach methodology (NAM) that has the capacity to address both hormonally regulated angiogenesis and EVT-driven remodeling. It offers a physiologically relevant platform for future research on decidualization, immune interactions, matrix mechanics, and drug repurposing for preeclampsia.