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- _3 value " Effects of hypoxia on molecular determinants of angiogenesis Angiogenesis is a complex process, involving multiple gene products expressed by different cell types, all contributing to an integrated sequence of events44. Consistent with a major role for hypoxia in the overall process, a large number of genes involved in different steps of angiogenesis are independently responsive to hypoxia in tissue culture. Examples include nitric oxide synthases involved in governing vascular tone, growth factors such as VEGF, angiopoietins, fibroblast growth factors and their various receptors, and genes involved in matrix metabolism, including matrix metalloproteinases, plasminogen activator receptors and inhibitors, and collagen prolyl hydroxylase16, 17, 18, 19, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 (Table 1). Similarly, many of the individual phenotypic processes in angiogenesis such as cell migration or endothelial tube formation can be induced by hypoxic tissue culture62, 63, 64. These analyses in isolated systems have sometimes apparently shown both positive and negative effects of hypoxia, for instance on endothelial proliferation65, 66, 67. It is not yet clear whether such phenomena reflect fundamentally different responses based on severity of hypoxia, or counter-regulatory controls that are normally integrated in a productive way." provenance.