INTRA-ARTERIAL INFUSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN NORMAL AND ISCHEMIC BRAINS HAS NO EFFECT ON ANGIOGENESIS
INTRODUCTION: Stimulation of angiogenesis in ischemic brains may be of major value in stroke therapy. Administration of vascular endothelial growth factor (VEGF) is considered particularly effective as an angiogenic factor for hypoxia-related injuries. We therefore quantitatively compared the effect of VEGF on microvessels of normal and ischemic brain cortices. Vascular parameters of microvessels measured included changes in numerical (NA), volume (Vv), surface (Sv) and length (Lv) densities along with diameter. METHODS: VEGF165protein at 1μg/ml was infused into the common carotid artery of normal and ischemic adult male Sprague-Dawley rats with a miniosmotic pump for 7 days at 1 μl/hr (VEGF infusion therefore 1 ηg/hr). Animals (n = 3 or 4 per group) were sacrificed at 7 days post-surgery. Ischemia was induced by occlusion of the middle cerebral artery for 4 hours. Vascular parameters were quantitated by light microscopic morphometry. Normal and ischemic brains not infused by VEGF served as controls. RESULTS: Mean and S.D. of the vascular parameters (NA [# of vessels/mm2]; Vv[%]; Sv [mm2/mm3]; Lv [mm/mm3];D [μm]) of the different groups are as follows: A) Normal brains (462 ± 63; 2.00± 0.2; 13.9 ± 1.7; 925 ± 127; 5.48 ± 0.5) B) Normal brains (480 ± 38; 2.25± 0.3; 14.9 ± 0.8; 961 ± 76; 4.98 ± 0.3) + VEGF C) Ischemic brains (471 ± 47; 2.06± 0.2; 14.3 ± 1.4; 942 ± 94; 5.11 ± 0.8) D) Ischemic brains (579 ± 102; 2.04 ± 0.3; 16.2 ± 2.7; 1159 ± 205; 4.64 ± 0.4) + VEGF There are no significant differences between the groups. CONCLUSIONS: Intra-arterial infusion of VEGF165 protein for 7 days at 1 ηg/hr has no effect on the vascular parameters of normal or ischemic cortices. Infusion of VEGF alone may not be sufficient for inducing neovascularization in intact brain. Further studies specifically testing the appropriate concentration, duration, VEGF isoform(s), manner of administration (protein, plasmids or viral vectors), use of combinational angiogenic factors along with permeability or other side effects are critical to ascertain the angiogenic merits of VEGF for stroke therapy.