Effect of physical and geometrical stimuli on microvascular dynamics

The microvasculature is not only a passive organ composed of pipes responsible for the delivery of blood to tissues. It is a highly dynamic organ that actively regulates the passage of nutrients and immune cells to the tissue. More specific, this regulation is bi-directional, where immune cells signal with the blood vessel cells to regulate the recruitment of immune cells to the vasculature, and the subsequent passage of immune cells through the vasculature into the tissue. This regulation of cell trafficking through the vasculature is deregulated in diseases such as atherosclerosis or in cancer, where cancer cells are trafficking through the vasculature in similar manners to immune cells. Besides cell-cell interactions, the dynamics of the vasculature can also be regulated by physical stimuli, such as the properties of the underlying extracellular matrix, the forces the vascular cells exert on each other through cytoskeletal activity, or the geometrical properties of the vascular network. We present mathematical models that elucidate how physical, together with molecular or cellular, stimuli can regulate the dynamic movements of the vasculature, the formations of gaps between vascular cells, and the resulting trafficking of immune or cancer cells through the vasculature. With this model, validated by experiments, we demonstrate that gaps in the vasculature preferentially occur at tricellular junctions, and that cancer cells consequently transmigrate at these locations. We also demonstrate how force distributions change in realistic 3D microvasculature, compared to 2D monolayers, and how this changes gap formation, leakage, and transmigration in 2 versus 3D.