Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor.
Vascular endothelial growth factor (VEGF) is essential for the differentiation of the primitive embryonic vascular system and has been implicated in the vascularization of organs. Recently, VEGF has also been proposed to play a role in neural development, neuroprotection, and adult neurogenesis. Here we have investigated the function of VEGF in the developing brain by cre-lox technology. We show that VEGF produced by the embryonic neuroectoderm is required for the vascularization and the development of the brain. Both the invasion and the directed growth of capillaries were severely impaired in the fore-, mid- and hindbrain of VEGF(lox/lox)/nestin-cre mouse embryos homozygous for a VEGF mutation in the neural tube. These observations demonstrate that VEGF, via local secretion by neural progenitors, induces brain angiogenesis and guides the growth of capillaries toward the ventricular zone. VEGF deficiency led to developmental retardation and progressive destruction of neural tissue in all brain regions. The defect was most pronounced in telencephalic structures, such as the hippocampus, and caused microcephaly. Taken together, the findings establish the critical importance of neuroectoderm-derived VEGF in the morphogenesis of the brain. VEGF acts as a key regulator of brain angiogenesis and provides instructive cues for the correct spatial organization of the vasculature.
Max-Plank-Institut für physiologische und klinische Forschung, Bad Nauheim, Germany.
Sabine
S
Raab
Heike
H
Beck
Andreas
A
Gaumann
Ali
A
Yüce
Hans-Peter
HP
Gerber
Karl
K
Plate
Hans-Peter
HP
Hammes
Napoleone
N
Ferrara
Georg
G
Breier
D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D002196:Capillaries / Q000473:pathology; D017930:Genes, Reporter; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D000860:Hypoxia; D020287:In Situ Nick-End Labeling; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D018919:Neovascularization, Physiologic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000473:pathology; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C045073:Cre recombinase; D019426:Integrases