Correlation of vascular endothelial growth factor to permeability of blood-brain barrier and brain edema during high-altitude exposure

BACKGROUND: Many studies have evaluated the role of vascular endothelial growth factor (VEGF) in traumatic brain edema and hemorrhagic brain edema. OBJECTIVE: To observe the effects of VEGF expression on permeability of the blood-brain barrier (BBB) during high-altitude and hypoxia exposure, and to investigate the correlation between VEGF expression and BBB permeability with regard to Evans blue staining and brain edema during high-altitude exposure. DESIGN, TIME AND SETTING: The randomized, controlled, animal study was performed at the Tanggula Etape, Central Laboratory of Chengdu Medical College, and Central Laboratory of General Hospital of Chengdu Military Area Command of Chinese PLA, China, from July 2003 to November 2004. MATERIALS: Quantitative RT-PCR kit (Sigma, USA), VEGF ELISA kit (Biosource, USA), and Evans blue (Jingchun, China) were acquired for this study. METHODS: A total of 180 Wistar rats were equally and randomly assigned to 15 groups: low-altitude (500 m), middle-altitude (2 880 m), high-altitude (4 200 m), super-high-altitude (5 000 m), 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 days of super high-altitude exposure. Wistar rats were exposed to various altitude gradients to establish a hypoxia model. MAIN OUTCOME MEASURES: Brain water content was calculated according to the wet-to-dry weight ratio. BBB permeability to Evans blue was determined by colorimetric method. VEGF mRNA and protein levels in brain tissues were detected using RT-PCR and double-antibody sandwich ELISA. RESULTS: Brain water content, BBB permeability to Evans blue, and VEGF mRNA and protein levels in brain tissues increased with increasing altitude and prolonged exposure to altitude. The greatest increase was determined on day 9 upon ascending 5 000 m. Simultaneously, VEGF expression positively correlated to BBB permeability of Evans blue and brain water content (r = 0.975, 0.917, P < 0.01). CONCLUSION: Increased VEGF protein and mRNA expression was responsible for increased BBB permeability, which may be an important mechanism underlying brain edema during high-altitude exposure.