VEGF induces cardiovascular malformation and embryonic lethality.

The essential function of vascular endothelial growth factor (VEGF) in embryonic angiogenesis has clearly been documented in murine embryos with targeted deletions of either VEGF or its receptors. The effects of VEGF in the organogenetic phase of development have not been studied to date. Therefore, we applied 0.7 to 0.9 microgram of VEGF via methylcellulose carriers into the midbrain or onto the right forelimb of 4.5-day-old quail embryos. Another group of embryos was treated with 1 microgram of platelet-derived growth factor and controls were carried out using carriers without any growth factor. VEGF-induced cardiovascular malformations resulted in embryonic lethality. The venous area of the vasculature was dilated in almost all organs. The heart was most seriously affected and showed typical characteristics of insufficiency. VEGF strongly increased endocardial cell proliferation and obviously induced impairment of the growth rates of myocardium and endocardium. The myocardium of the ventricles was extremely thin, and septation defects were observed. As a result of the disturbed outflow, the atria were extremely dilated and thin-walled. The morphology of the hearts was reminiscent of that observed in congenital malformations such as Uhl's and Osler's syndromes. Our results show that expression of VEGF has to be tightly controlled during development.