Imaging the Dynamic Interaction Between Sprouting Microvessels and the Extracellular Matrix

Thorough understanding of growth and evolution of tissue vasculature is fundamental to many fields of medicine including cancer therapy, wound healing, and tissue engineering. Angiogenesis, the growth of new vessels from existing ones, is dynamically influenced by a variety of environmental factors, including mechanical and biophysical factors, chemotactic factors, proteolysis, and interaction with stromal cells. Yet, dynamic interactions between neovessels and their environment are difficult to study with traditional fixed time imaging techniques. Advancements in imaging technologies permit time-series and volumetric imaging, affording the ability to visualize microvessel growth over 3D space and time. Time-lapse imaging has led to more informative investigations of angiogenesis. The environmental factors implicated in angiogenesis span a wide range of signals. Neovessels advance through stromal matrices by forming attachments and pulling and pushing on their microenvironment, reorganizing matrix fibers, and inducing large deformations of the surrounding stroma. Concurrently, neovessels secrete proteolytic enzymes to degrade their basement membrane, create space for new vessels to grow, and release matrix-bound cytokines. Growing neovessels also respond to a host of soluble and matrix-bound growth factors, and display preferential growth along a cytokine gradient. Lastly, stromal cells such as macrophages and mesenchymal stem cells interact directly with neovessels and their surrounding matrix to facilitate sprouting, vessel fusion, and tissue remodeling. This review highlights how time-lapse imaging techniques advanced our understanding of the interaction of blood vessels with their environment during sprouting angiogenesis. The technology provides means to characterize the evolution of microvessel behavior, providing new insights and holding great promise for further research on the process of angiogenesis.