Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor

Sabine Raab; Heike Beck; Andreas Gaumann; Ali Yüce; Hans-Peter Gerber; Karl Plate; Hans-Peter Hammes; Napoleone Ferrara; Georg Breier

doi:10.1160/TH03-09-0582

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(03): 595-605
DOI: 10.1160/TH03-09-0582

Endothelium and Vascular Development

Schattauer GmbH

Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor

Sabine Raab

¹Max-Planck-Institut für physiologische und klinische Forschung, Bad Nauheim, Germany

,

Heike Beck

²Neurologisches Institut der Universität, Frankfurt/Main, Germany

,

Andreas Gaumann

¹Max-Planck-Institut für physiologische und klinische Forschung, Bad Nauheim, Germany

,

Ali Yüce

³Universitätsklinikum, Giessen, Germany

,

Hans-Peter Gerber

⁴Genentech, San Francisco, California, USA

,

Karl Plate

²Neurologisches Institut der Universität, Frankfurt/Main, Germany

,

Hans-Peter Hammes

⁵V. Medizinische Klinik, Mannheim, Germany

,

Napoleone Ferrara

⁴Genentech, San Francisco, California, USA

,

Georg Breier

¹Max-Planck-Institut für physiologische und klinische Forschung, Bad Nauheim, Germany

⁶Universitätsklinikum Carl Gustav Carus an der TU Dresden, Dresden, Germany

› Author Affiliations

Abstract

Summary

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-, midand hindbrain of VEGFlox/lox/nestin-cre mouse embryos homozygous for a VEGF mutation in the neural tube. These observations demonstrate thatVEGF, 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.

Keywords

Angiogenesis - brain development - microcephaly - retina - VEGF

Full Text

References

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