Under normal circumstances the endothelium of retinal capillaries divide infrequently. This fact suggests that there is a very powerful mechanism which controls growth at the microvascular level. Although the exact nature of this mechanism is not known, it is likely that a number of factors contribute to vascular growth control. Clinical and experimental observations have implicated the following four factors in the regulation of capillary growth: capillary integrity, cell-cell interactions, the nutrient supply (oxygen) and the extracellular matrix. Because of the inaccessibility of the capillary it is difficult to investigate these factors in vivo. However, using cultures of microvascular endothelial cells (EC) and pericytes the contribution of each of these variables to the control process can be investigated. Specifically, this application proposes the following: (1) To characterize pericyte function with particular emphasis on contractile potential using affinity-purified antibodies to contractile proteins, time-lapse video microscopy and computer-assisted quantitation. (2) To investigate the interactions between capillary EC and pericytes with respect to their influence on capillary growth using conditioned media and co-cultures studies. (3) To elucidate the differential effects of oxygen on capillary EC and pericytes and to investigate the mechanism of oxygen damage to EC. The cells will be grown under altered oxygen concentrations and examined for changes in enzymes involved in protection against oxygen by-products. The effect of vessel source and age and cell density on sensitivity to oxygen will be assessed. Finally, the effect of oxygen exposure on the ability of the cells to migrate will be investigated using migration assays and specific cytoskeletal probes. (4) To investigate the interactions of pericytes and EC with basement membrane-associated glycosaminoglycans by quantitating and characterizing the specific binding of hyaluronic acid and heparin-like glycosaminoglycans to EC and pericytes in vitro. The ultimate goal of these studies is to identify and characterize the individual factors which contribute to microvascular growth control. By providing specific information on the role of microvascular cells, the results of these studies will add to our understanding of the multiple factors which play a role in retinal neovascularization.
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