Angiogenesis, i.e. the formation of blood vessels by endothelial cells, plays an important role in the pathogenesis of several vascular diseases and of tumor growth. The goal of this study is to elucidate the role of the extracellular matrix (ECM) in the regulation of angiogenesis. Studies from our laboratory and from others have shown that fibronectin, laminin and type IV collagen, which are major components of the microvascular ECM, accumulate around developing microvessels in different amounts at different, i stages of angiogenesis. These molecules have distinct effects on the attachment, spreading, migration and proliferation of endothelial cells on two-dimensional plastic surfaces but their function during angiogenesis in three-dimensional gels of fibrin or type I collagen, i.e. in a setting that simulates the in vivo environment is poorly understood. Our hypothesis is that the growth and morphogenesis of microvessels is modulated by changes in the composition of the microvascular ECM during angiogenesis. To investigate this hypothesis we will use the rat aortic ring model of angiogenesis in vitro, which was first developed in our laboratory. Rings of rat aorta or isolated endothelial cells will be cultured in chemically defined gels of fibrin or type I collagen containing known amounts of fibronectin, laminin and/or type IV collagen. Angiogenesis will be evaluated using image analysis, autoradiographic and immunohistochemical techniques. The reconstituted matrices will be characterized with electro- phoretic,Western blotting and immunohistochemical techniques.
Specific aims : 1. To determine the concentrations of fibronectin, laminin or type IV collagen that have a maximum stimulatory or inhibitory effect on the sprouting, canalization and maturation of microvessels and to investigate if these molecules have additive, synergistic or antagonistic effects on angiogenesis. 2. To investigate the hypothesis that fibronectin, laminin and/or type IV collagen regulate angiogenesis by influencing the direction of endothelial sprouting. 3. To evaluate the effect of fibronectin, laminin and/or type IV collagen on the attachment, spreading and proliferation of isolated endothelial cells in gels of fibrin or type I collagen.
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