The microvasculature consists of endothelial cells (EC), which form the capillary tube, and abluminally located pericytes. In the retina (and the central nervous system, in general), a third cell type, the astrocyte, associates with the microvasculature. This application is based on the hypothesis that heterotypic intercellular interactions (i.e. between unlike cell types) play an important role in the assembly and function of the retinal microvasculature. The proposed studies focus on the two different heterotypic interactions that take place in retinal microvessels: EC-pericyte and EC-astrocyte. Embryological data suggest that EC recruit mural cells (pericytes and smooth muscle cells), and influence their subsequent behavior. We have successfully modeled this process in vitro. Our data indicate that EC recruit pericyte precursors (10T1/2 cells as undifferentiated mesenchymal cells) and direct their differentiation into mural cells, We propose to extend these studies in the following aims: (1) to continue to develop and characterize. an in vitro model of blood vessel assembly, with attention to the differentiation and proliferation of EC and pericytes; (2) to confirm the relevance of the in vitro observations using in vivo models and, (3) to elucidate the mechanism whereby TGF- beta induces differentiation of pericytes. Furthermore, convincing data indicate that astrocytes contribute to induction of the blood retinal barrier, a highly specialized, differentiated function of the retinal microvasculature. We have established cultures of rat astrocytes and EC and propose (4) to investigate the nature of EC-astrocyte interactions and to elucidate their role in determining the characteristics of the blood retinal barrier. Results of these studies will contribute to the overall objective of this research program which is to elucidate the cellular mechanisms that regulate retinal microvascular growth and function.
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