| Abstrakt: |
Angiogenesis is a multi-factorial process that involves different cell types and a number of cytokines and growth factors. Physiological angiogenesis is characterized by the existence of a delicate balance between pro-angiogenic and anti-angiogenic factors. In an in vivo setting, pro-angiogenic stimuli such as endothelial-specific mitogenic factors and extracellular matrix (ECM)- degrading enzymes must be tightly regulated and locally constrained. Differentiation factors, protease inhibitors, and the elements involved in reconstruction of ECM and recruitment of mural cells must be elicited in an appropriate temporal and spatial arrangement. Overexpression of angiogenesis-activating factors may cause hyper-vascularization. However, deficiency or disarray in expression of anti-angiogenic factors may result in leaky vessels, unstable capillaries, and formation of dysfunctional neovascular tufts as seen in retinopathy of prematurity, diabetic retinopathy, or other conditions of retinal neovascularization. In other words, pathological angiogenesis is characterized not only by excesses in pro-angiogenic factors but also an insufficiency in anti-angiogenic, pro-differentiation factors. To better understand pathological angiogenesis, our experimental models should be able to dissect the dissolution phase of the angiogenic process from the resolution phase. In an in vivo model of pathological angiogenesis, these two components occur in close spatial and temporal proximity and thus are difficult to dissect. By using in vitro models, it is possible to begin with the most basic elements in order to reconstitute physiological and pathological conditions and compare each step of the process. Retina explants, primary cultures of retinal vascular endothelial cells, and cocultures of endothelial and mural cells, together with gene transfer techniques, have enabled us to analyze the functional roles of cytokines, growth factors, and extracellular proteolytic enzymes involved in the angiogenic process and to develop assay systems for testing the efficacy of pharmaceutical reagents that specifically block intracellular signaling pathways and transcription factors. Finally, use of endothelial and mural cells isolated from transgenic animals in tissue culture models aids in defining gene functions and elucidating the mechanisms of their regulation. [ABSTRACT FROM AUTHOR] |
