VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain
Zheng Gang Zhang, … , Nicholas van Bruggen, Michael Chopp
Zheng Gang Zhang, … , Nicholas van Bruggen, Michael Chopp
Published October 1, 2000
Citation Information: J Clin Invest. 2000;106(7):829-838. https://doi.org/10.1172/JCI9369.
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Article

VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain

Abstract

VEGF is a secreted mitogen associated with angiogenesis and is also a potent vascular permeability factor. The biological role of VEGF in the ischemic brain remains unknown. This study was undertaken to investigate whether VEGF enhances cerebral microvascular perfusion and increases blood-brain barrier (BBB) leakage in the ischemic brain. Using magnetic resonance imaging (MRI), three-dimensional laser-scanning confocal microscope, and functional neurological tests, we measured the effects of administrating recombinant human VEGF165 (rhVEGF165) on angiogenesis, functional neurological outcome, and BBB leakage in a rat model of focal cerebral embolic ischemia. Late (48 hours) administration of rhVEGF165 to the ischemic rats enhanced angiogenesis in the ischemic penumbra and significantly improved neurological recovery. However, early postischemic (1 hour) administration of rhVEGF165 to ischemic rats significantly increased BBB leakage, hemorrhagic transformation, and ischemic lesions. Administration of rhVEGF165 to ischemic rats did not change BBB leakage and cerebral plasma perfusion in the contralateral hemisphere. Our results indicate that VEGF can markedly enhance angiogenesis in the ischemic brain and reduce neurological deficits during stroke recovery and that inhibition of VEGF at the acute stage of stroke may reduce the BBB permeability and the risk of hemorrhagic transformation after focal cerebral ischemia.

Authors

Zheng Gang Zhang, Li Zhang, Quan Jiang, Ruilan Zhang, Kenneth Davies, Cecylia Powers, Nicholas van Bruggen, Michael Chopp

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(a) The percentage of time that rats persisted on the rotarod after isch...
(a) The percentage of time that rats persisted on the rotarod after ischemia compared with the preischemic value as a function of time of stroke. Rotarod test was performed at 2, 7, 14, and 28 days after stroke on the ischemic rats treated with rhVEGF165 or saline initiated at 48 hours after ischemia. Treatment with rhVEGF 165 (triangles; n = 7) significantly (AP < 0.05 or BP < 0.01) increases time spent on the rotarod compared with the saline-treated group (circles; n = 10). Cerebral vessels and FITC-dextran–perfused cerebral microvessels from the saline-treated rat (b–d) and the rhVEGF165-treated rat (e–g) 28 days after the right MCA occlusion. Dorsal view of the right and left hemisphere vessels (b and e), a lateral view of the right hemisphere vessels (c and f), and FITC-dextran–perfused cerebral microvessels in the penumbra of the cortex (d and g). More vessels in the ipsilateral ischemic border zone (e, arrows, and f) and more FITC-dextran–perfused vessels (g) were observed in the rhVEGF165-treated rat compared with that in the saline-treated rat (b–d). Bar = 2 mm in f for b, c, e, and f; bar = 200 μm in g for d and g. Rats were decapitated one minute after injection of FITC-dextran and their brains were rapidly removed from the severed heads and digitized at 8× magnification (for panels b, c, e, and f) using an MCID image analysis system (Imaging Research, St. Catherines, Canada). After digitization the brains were placed in 4% paraformaldehyde at 4°C for 48 hours (for panels d and g).