Attenuation of Brain Response to Vascular Endothelial Growth Factor-Mediated Angiogenesis and Neurogenesis in Aged Mice

Background and Purpose - Alterations of neuroangiogenic response play important roles in the development of aging-related neurodisorders and affect gene-based therapies. We tested brain response to vascular endothelial growth factor (VEGF) in aged mice. Methods - Adeno-associated viral vector (AAV)-VEGF, an adeno-associated viral vector expressing VEGF, was injected into the brain of 3-, 12-, and 24-month-old mice. AAV-LacZ-injected mice were used as controls (n = 6). Before euthanasia at 6 weeks after vector injection, the mice were intraperitoneally injected with 5-bromodeoxyuridine for 3 consecutive days. The vascular density and the number of neuroprogenitors were analyzed. Results - Injection of AAV-VEGF increased the vascular density in the brain of 3-, 12-, and 24-month-old mice by 22% +/- 7% (AAV-VEGF: 320 +/- 15 per 10 x field versus AAV-LacZ: 263 +/- 8, P < 0.05), 20% +/- 8 (AAV-VEGF: 300 +/- 9 versus AAV-LacZ: 250 +/- 11, P < 0.05), and 7% +/- 16% (AAV-VEGF: 257 +/- 27 versus AAV-LacZ: 236 +/- 13, P = 0.283), respectively. There were more VEGF receptor-positive neuroprogenitors in the subventricular zone of AAV-VEGF-injected 3-(22 +/- 2) and 12-month-old mice (21 +/- 5) than that of 24-month-old mice (7 +/- 1). More 5-bromodeoxyuridinepositive endothelial cells and neuroprogenitors were detected around the injection site and subventricular zone of 3( 13 +/- 4) and 12-month-old mice (14 +/- 5) than that of 24-month-old mice (1 +/- 1). VEGF receptor 2 was upregulated in AAV-VEGF-injected brains of 3- and 12-month-old mice, but not in 24-month-old mice. Conclusion - The angiogenic and neurogenic response to VEGF stimulation is attenuated in the aged mouse brain, which may be due to reduced VEGF receptor activity. (Stroke. 2009; 40: 3596-3600.)