BLOOD FLOW AND STRUCTURAL ADAPTATION IN MICROCIRCULATION PROJECT SUMMARY Angiogenesis (growth of new blood vessels) is central to a wide range of physiological and pathological processes, including development, growth, exercise, estrus cycle, wound healing, collateral formation following ischemia, neovascular macular degeneration, and tumor growth. Much research on angiogenesis has focused on the cellular and molecular processes of vessel formation. How networks with adequate functional properties are formed, through angiogenesis, adaptation (remodeling) and pruning (removal) of vessels, has received less attention. This project uses theoretical models to address the following question: How do the processes of angiogenesis, structural adaptation and pruning generate vascular structures that meet the functional needs of the tissue? The developing retina of the neonatal mouse is used extensively as an animal model for studying angiogenesis. After birth, the retinal microcirculation spreads rapidly by sprouting angiogenesis to form a primary plexus covering the inner surface of the retina by P9 (postnatal day 9). During P8 to P14, sprouts from this network dive into the retina, forming new networks at two different levels within the retina. The availability of a large amount of data from this well-characterized experimental system provides a strong basis for developing detailed theoretical models, and for using these models to determine the roles of specific biological mechanisms in the formation of functional network structures. Specific Aim 1 is to develop two-dimensional models for the growth of the primary retinal plexus during P1-P9. A segment-based approach will be used to describe network structure, growth, adaptation and pruning, and continuous field models will be used for oxygen and growth factor diffusion. The following biological mechanisms will be included: production of growth factors in hypoxic regions; stimulation of sprouting angiogenesis by growth factors; lateral inhibition of tip cell formation to control sprout density; growth of sprouts led by endothelial tip cells; guidance of sprouts by the preexisting network of astrocytes; structural adaptation of vessel diameters in response to wall shear stress, pressure, metabolic conditions and conducted responses; and pruning of redundant vessels. The questions to be addressed are: What is the role and importance of each of these biological mechanisms? What are the effects of its modulation or abolition? Model predictions will be compared with observations in wild-type and genetically modified animals. Specific Aim 2 is to develop three- dimensional models for the growth of the deeper plexuses and the regression of the primary plexus during P8-P14. The modeling approach will be extended to three dimensions. Effects of variations in oxygen and growth factor levels through the retina will be included. These studies will provide insight into the mechanisms by which functional vascular networks are generated with remarkable speed in the neonatal mouse retina, suggest new directions for experimental work on control of vascular structure, and form a rational basis for developing interventions to control angiogenesis for therapeutic purposes.