A perfusable first-generation endometrial microvascular model to study human spiral artery remodeling in pregnancy

Invasive placental cells, extravillous trophoblasts (EVT), remodel maternal vasculature to meet metabolic needs of the growing fetus. Dysregulation of spiral artery remodeling (SAR) is a characteristic of preeclampsia (PE), a severe pregnancy-related condition. We developed a modular new approach methodology (NAM) of human endometrial-specific vascular networks in a polystyrene (PS) microfluidic chip to recapitulate the intricate endometrial vascular microenvironment to investigate SAR. We leveraged the self-assembly of human endometrial microvascular endothelial cells (HEMEC) and normal human lung fibroblasts (NHLF) to successfully develop patent endometrial vascular networks after 3 days of culture. Exogenous proangiogenic factors significantly improved vascular density while maintaining intrinsic endometrial vascular properties. Treatments of menstrual cycle phase-specific hormones differentially affected endometrial vascular density, diameter, permeability, and endogenous secretions of proangiogenic proteins. We evaluated integration potential of EVT cell lines HTR8/SVneo and JEG-3. We measured decreased barrier function and observed increased presence of apoptotic HEMECs after 3 days of tri-culture with JEG-3 cells, whereas HTR8/SVneo-induced apoptosis remained statistically unchanged across days 1 and 3 of integration. Moreover, we confirm HTR8/SVneo and JEG-3 cells differentially interact with HEMEC vasculature and the surrounding perivascular niche. These studies demonstrate the utility of our model to study endometrial vascularization and EVT remodeling.