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PA D'Amore, LJ Massingham, SR Smith, AB Roberts, E Piek, DC Darland; Pericyte Production of VEGF is Differentiation-Dependent and Mediates Endothelial Survival . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1932.
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Purpose: Pericytes have been suggested to play a role in vessel formation and there is increasing evidence that pericytes influence vessel stability. This is apparent in the altered cell function and cell death that characterizes non-proliferative retinopathy following the loss of pericytes. The goal of these studies was to test the hypothesis that induction of mesenchymal cell differentiation to pericytes/smooth muscle (SM) cells is accompanied by the induction of VEGF expression by the pericytes and that this VEGF mediates endothelial cell (EC) survival and stability. Methods: Cocultures of EC and multipotent mesenchymal (10T1/2) cells and genetically modified mouse embryo fibroblasts were used to model the heterotypic cell-cell interactions that take place in vessels. The production of VEGF was quantified by ELISA and the role of VEGF in vessel stability was assessed in two dimensional cocultures by measuring apoptosis and in three-dimensional cultures by examining the formation of capillary-like structures. Results: Coculture of EC and 10T1/2 cells led to the differentiation of 10T1/2 cells to a pericyte lineage (as evidenced by the expression of SM proteins) and to the induction of VEGF expression. The increase in VEGF was dependent on contact between the EC and 10T1/2 cells. The induction of VEGF was due to the activation of TGFß in the cocultures; coculture of EC with mesenchymal cells isolated from mice deficient in SMAD3, which mediates a component of TGFß signalling, did not yield elevated VEGF. A majority of the VEGF in the cocultures was cell- and or matrix-associated. The sequestration of the VEGF is mediated by heparan sulfate proteoglycans, as treatment of the cells with high salt, suramin, protamine or heparin led to a release of a significant amount of VEGF. Inhibition of VEGF in the cocultures led to a 75% increase in EC apoptosis relative to cocultures treated with irrelevant IgG, indicating a role in EC survival. Conclusion: Observations of EC-mesenchymal cell cocultures indicate that differentiated pericytes produce VEGF, which remains cell-associated and acts in a juxtacrine/paracrine manner as a survival and/or stabilizing factor for EC in newly formed vessels.
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