Modeling Geometric and Hemodynamic Cues in Cardiovascular Biology

Abstract

From the capillaries to the aorta, the behavior of endothelial cells lining the vasculature is guided by local hemodynamic conditions that can induce both development and disease. Much remains unknown, however, about how these local conditions are integrated by endothelial cells to produce both endothelial and parenchymal responses. The lack of in vitro models that enable careful perturbation with the diversity of biophysical conditions present in vivo has been a barrier to a deeper understanding of these responses. The following dissertation reports on the development of model systems to further understand the role of geometric and hemodynamic cues on the response of endothelial cells to flow and their interactions with parenchymal populations. We first develop a spiral microvessel model that enables precise control of vessel curvature and torsion, showing that modification of these geometric features can alter the response of endothelial cells and shedding light on the role of structural heterogeneity in vascular biology. We further interrogate these curvature induced effects in a large vessel aneurysm model, demonstrating changes in endothelial phenotype are associated with geometric and hemodynamic conditions. Based on insights from these experiments we then investigate the role of pressure in endothelial flow sensing and vascular remodeling. We find that pressure conditions help shape the endothelial response to shear stress and can also guide vascular remodeling in engineered tissues. To enable further study of pressure induced effects we finally develop a perfusable model of early heart development in which pressure stimulated endothelial-cardiomyocyte interactions can be interrogated. By modeling these diverse geometric and hemodynamic features we gain valuable new insights into endothelial biology and provide new tools for investigating endothelial responses to blood flow and interactions with cardiovascular tissues.