Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

Ferrara, Napoleone
Carver-Moore, Karen
Chen, Helen
Dowd, Mary
Lu, Lucy
O'Shea, K. Sue
Powell-Braxton, Lyn
Hillan, Kenneth J.
Moore, Mark W.

Departments of Cardiovascular Research, Molecular Biology and Bioanalytical Technology, Genentech Inc., 460 Point San Bruno Boulevard, South San Francisco, California 94080, USA.
(O'Shea) Department of Anatomy and Cell Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Nature 380(6573):p 439-442, April 4, 1996.

ANGIOGENESIS is required for a wide variety of physiological and pathological processes *RF 1*. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF) is a major mediator of pathological angiogenesis . 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 . Mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5 (). However, ligand(s) other than VEGF might activate such receptors . 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.