Brain Advance Access originally published online on October 27, 2004
Brain 2005 128(1):52-63; doi:10.1093/brain/awh325
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Brain Vol. 128 No. 1 © Guarantors of Brain 2004; all rights reserved
VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena
1 Department of Neurology and 2 Department of Nuclear Medicine, University Hospital Zurich, 3 Institute of Physiology, University of Zurich, Zurich, Switzerland and 4 Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany
Correspondence to: Hugo H. Marti, University of Heidelberg, Institute of Physiology and Pathophysiology, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany E-mail: hugo.marti{at}pio1.uni-heidelberg.de
Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) is a clinically promising strategy in ischaemic disease. The pathophysiological consequences of enhanced vessel formation, however, are poorly understood. We established mice overexpressing human VEGF165 under a neuron-specific promoter, which exhibited an increased density of brain vessels under physiological conditions and enhanced angiogenesis after brain ischaemia. Following transient intraluminal middle cerebral artery (MCA) occlusions, VEGF overexpression significantly alleviated neurological deficits and infarct volume, and reduced disseminated neuronal injury and caspase-3 activity, confirming earlier observations that VEGF has neuroprotective properties. Brain swelling was not influenced in VEGF-overexpressing animals, while sodium fluorescein extravasation was moderately increased, suggesting that VEGF induces a mild blood–brain barrier leakage. To elucidate whether enhanced angiogenesis improves regional cerebral blood flow in the ischaemic brain, [14C]iodoantipyrine autoradiography was performed. Autoradiographies revealed that VEGF induces haemodynamic steal phenomena with reduced blood flow in ischaemic areas and increased flow values only outside the MCA territory. Our data demonstrate that VEGF protects neurons from ischaemic cell death by a direct action rather than by promoting angiogenesis, and suggest that strategies aiming at increasing vascular density in the whole brain, e.g. by VEGF overexpression, may worsen rather than improve cerebral haemodynamics after stroke.
* These authors contributed equally to this work
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