HETEROZYGOUS EMBRYONIC LETHALITY INDUCED BY TARGETED INACTIVATION OF THE VEGF GENE

ANGIOGENESIS is required for a wide variety of physiological and patho logical processes(1). The endothelial cell-specific mitogen vascular e ndothelial growth factor (VEGF)(2,3) is a major mediator of pathologic al angiogenesis(4-6). Also, the expression of VEGF and its two recepto rs, 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 ina ctivate either receptor die in utero between days 8.5 and 9.5 (refs 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 ge ne in embryonic stem cells. Here we report the unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between da ys 11 and 12. Angiogenesis and blood-island formation were impaired, r esulting in several developmental anomalies. Furthermore, VEGF-null em bryonic stem cells exhibit a dramatically reduced ability to form tumo urs in nude mice.