Agent‐Based Model of Pericyte Response to Platelet‐Derived Growth Factor‐BB from Sprouting Endothelial Cells in the Developing Mouse Retina

During blood vessel development, cross‐talk between the vascular endothelial growth factor (VEGF) and Notch pathways, among others, coordinates the sprouting of endothelial “tip” cells from existing vessels. These tip cells in turn secrete platelet‐derived growth factor‐BB (PDGF‐BB) to recruit pericytes for the stabilization of nascent vessel branches1. We therefore hypothesize that PDGF‐BB production from endothelial cells must be tightly regulated such that pericyte recruitment closely matches the rate of endothelial tip cell formation. To test this hypothesis, we expanded our recently published model of angiogenesis2 in the developing mouse retina to include endothelial cell production of, and pericyte responsiveness to, PDGF‐BB. Methods Our previous agent‐based model (ABM) was implemented in NetLogo and captures the effect of pericytes on endothelial tip cell formation at the angiogenic front of the developing mouse retina2. Here, we incorporated additional rules to govern (i) PDGF‐BB secretion from endothelial cells, with tip cells increasing their production, (ii) pericyte migration, and (iii) pericyte movement towards regions with the highest PDGF‐BB concentrations. In addition to monitoring output levels of each molecular species, the ABM endpoints included the spatial position of each cellular agent, yielding insight into relative locations of endothelial cells, tip cells, and migrating pericytes. Results Incorporation of the additional rules governing PDGF‐BB and pericytes did not cause any abnormal changes to the previously validated cell behaviors within by our published model. One important parameter that we explored in initial simulations was the rate of PDGF‐BB secretion from endothelial tip cells. Interestingly, if the tip cell PDGF‐BB secretion rate was relatively high, neighboring pericytes would ensheath tip cells such that outward migration of these endothelial cells was limited, or completely blocked, even though they retained other tip cell characteristics, such as higher expression of VEGF receptor 2. In addition, the number of endothelial tip cells did not change across a range from low to high PDGF‐BB production rates. Discussion Using ABM to simulate the key growth factor signaling pathways (VEGF, Notch, PDGF‐BB) and cell behaviors, including pericyte‐endothelial cell interactions, that contribute to retinal vascular development has led to one intriguing new hypothesis that can be tested experimentally: if endothelial cell migration rate outward from an existing vessel outpaces the tip cell production rate of PDGF‐BB, pericyte migration along newly formed branches will be impaired, which could adversely affect neo‐vessel stability/longevity. Testing this, and other related hypotheses generated by the ABM, will likely yield new insights into basic principles for normal blood vessel formation, as well as into pathological settings in which high levels of angiogenic growth factors fail to generate functional new blood vessels. Additionally, this computational model will inspire the generation of new experimental tools and models to validate the findings from these simulations. Support or Funding Information University of Virginia‐VIrginia Tech Carilion Seed Fund (to J.C. and S.P.), NIH R56HL133826 (to J.C.) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .