VEGF is required for growth and survival in neonatal mice

We employed two independent approaches to inactivate the angiogenic protein VEGF in newborn mice: inducible, CreloxP- mediated gene targeting, or admi nistration of mFlt(1-3)-IgG, a soluble VEGF receptor chimeric protein. Part ial inhibition of VEGF achieved by inducible gene targeting resulted in inc reased mortality, stunted body growth and impaired organ development, most notably of the liver. Administration of mFlt(1-3)-IgG, which achieves a hig her degree of VEGF inhibition, resulted in nearly complete growth arrest an d lethality, Ultrastructural analysis documented alterations in endothelial and other cell types. Histological and biochemical changes consistent with liver and renal failure were observed. Endothelial cells isolated from the liver of mFlt(l-3)-IgG-treated neonates demonstrated an increased apoptoti c index, indicating that VEGF is required not only for proliferation but al so for survival of endothelial cells. However, such treatment resulted in l ess significant alterations as the animal matured, and the dependence on VE GF was eventually lost some time after the fourth postnatal week, Administr ation of mFlt(l-3)-IgG to juvenile mice failed to induce apoptosis in liver endothelial cells. Thus, VEGF is essential for growth and survival in earl y postnatal life. However, in the fully developed animal, VEGF is likely to be involved primarily in active angiogenesis processes such as corpus lute um development.