Preconditioning with VEGF Enhances Angiogenic and Neuroprotective Effects of Bone Marrow Mononuclear Cell Transplantation in a Rat Model of Chronic Cerebral Hypoperfusion.

Abstract

Bone marrow mononuclear cell (BMMNC) transplantation is a promising therapy for brain ischemia. However, BMMNCs are few in number, and a limited time window is available during which they can penetrate the blood-brain barrier (BBB) and migrate to the brain. We investigated whether vascular endothelial growth factor (VEGF) can facilitate BMMNC migration into the ischemic brain and enhance their therapeutic effect in a rat model of chronic cerebral hypoperfusion. First, we assessed the impact of VEGF on the BBB of rats that had undergone permanent bilateral occlusion of the common carotid arteries (2VO). Then, we transplanted BMMNCs into 2VO rats pretreated with intracerebroventricular VEGF or vehicle. We examined cognitive function with the Morris water maze test, BMMNC migration by immunofluorescence analysis, and cytokine levels in the peripheral blood by enzyme-linked immunosorbent assay (ELISA). Angiogenesis and neural degeneration were evaluated by staining tissue with Ki67/lectin or Fluoro-Jade B. We found that at a dose of 0.2μg/rat, VEGF significantly increased BBB permeability without causing brain edema in 2VO rats. VEGF + BMMNC-treated rats had more BMMNC migration in the ischemic brain, better learning and memory, greater proliferation of vessels, and fewer degenerating neurons than did BMMNC-treated rats. Pretreatment with VEGF receptor inhibitor SU5416 significantly decreased BMMNC migration and abolished the therapeutic effect of BMMNC transplantation. We conclude that preconditioning with an appropriate dose of VEGF can enhance the therapeutic efficacy of BMMNC transplantation in 2VO rats, possibly by facilitating BMMNC migration into the ischemic brain.