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ANGIOGENESIS is required for a wide variety of physiological and pathological processes *RF 1*. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF) [2,3] is a major mediator of pathological angiogenesis [4-6]. Also, the expression of VEGF and its two receptors, Flt-1 and Flk-1/KDR, is related to the formation of blood vessels in mouse and rat embryos [7-10]. Mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5 ( [11,12]). However, ligand(s) other than VEGF might activate such receptors [13,14]. To assess the role of VEGF directly, we disrupted the VEGF gene in embryonic stem cells. Here we report the unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12. Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. Furthermore, VEGF-null embryonic stem cells exhibit a dramatically reduced ability to form tumours in nude mice.

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