BLOOD FLOW AND STRUCTURAL ADAPTATION IN MICROCIRCULATIONPROJECT SUMMARYAngiogenesis (growth of new blood vessels) is central to a wide range of physiological and pathologicalprocesses including development growth exercise estrus cycle wound healing collateral formation followingischemia neovascular macular degeneration and tumor growth. Much research on angiogenesis has focusedon the cellular and molecular processes of vessel formation. How networks with adequate functional propertiesare formed through angiogenesis adaptation (remodeling) and pruning (removal) of vessels has receivedless attention. This project uses theoretical models to address the following question: How do the processesof angiogenesis structural adaptation and pruning generate vascular structures that meet thefunctional needs of the tissue? The developing retina of the neonatal mouse is used extensively as ananimal model for studying angiogenesis. After birth the retinal microcirculation spreads rapidly by sproutingangiogenesis to form a primary plexus covering the inner surface of the retina by P9 (postnatal day 9). DuringP8 to P14 sprouts from this network dive into the retina forming new networks at two different levels within theretina. The availability of a large amount of data from this well-characterized experimental system provides astrong basis for developing detailed theoretical models and for using these models to determine the roles ofspecific biological mechanisms in the formation of functional network structures. Specific Aim 1 is to developtwo-dimensional models for the growth of the primary retinal plexus during P1-P9. A segment-basedapproach will be used to describe network structure growth adaptation and pruning and continuous fieldmodels will be used for oxygen and growth factor diffusion. The following biological mechanisms will beincluded: production of growth factors in hypoxic regions; stimulation of sprouting angiogenesis by growthfactors; lateral inhibition of tip cell formation to control sprout density; growth of sprouts led by endothelial tipcells; guidance of sprouts by the preexisting network of astrocytes; structural adaptation of vessel diameters inresponse to wall shear stress pressure metabolic conditions and conducted responses; and pruning ofredundant vessels. The questions to be addressed are: What is the role and importance of each of thesebiological mechanisms? What are the effects of its modulation or abolition? Model predictions will be comparedwith 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 plexusduring P8-P14. The modeling approach will be extended to three dimensions. Effects of variations in oxygenand growth factor levels through the retina will be included. These studies will provide insight into themechanisms by which functional vascular networks are generated with remarkable speed in the neonatalmouse retina suggest new directions for experimental work on control of vascular structure and form arational basis for developing interventions to control angiogenesis for therapeutic purposes.