Over-expression of Slit2 induces vessel formation and changes blood vessel permeability in mouse brain.

Aim: To investigate the effect of the axon guidance cue Slit2 on the density of blood vessels and permeability of the blood-brain barrier in mouse brain.

Methods: hSlit2 transgenic mouse line was constructed, and the phenotypes of the mice were compared with wild-type mice in respect to the lateral ventricle (LV), ventricle pressure, and the choroids plexus. An in vivo Miles permeability assay and an amyloid-β permeability assay were used to assess the permeability of brain blood vessels. Brain vessel casting and intracerebral hemorrhage models were built to investigate vessel density in the transgenic mice. An in vitro permeability assay was used to test whether Slit2 could change the permeability and tight junctions of blood vessel endothelial cells.

Results: Hydrocephalus occurred in some transgenic mice, and a significantly larger lateral ventricle area and significantly higher ventricle pressure were observed in the transgenic mice. The transgenic mice displayed changed construction of the choroids plexus, which had more micro vessels, dilated vessels, gaps between epithelial cells and endothelial cells than wild-type mice. Slit2 significantly increased brain vessel density and the permeability of brain vessels to large molecules. These blood vessels were more sensitive to cues that induce brain hemorrhage. At the cellular level, Slit2 disturbed the integrity of tight junctions in blood vessel endothelial cells and improved the permeability of the endothelial cell layer. Thus, it promoted the entry of amyloid-β peptides from the serum into the central nervous system, where they bound to neurons.

Conclusion: Slit2 increases vessel density and permeability in the brains of transgenic mice. Thus, Slit2 induces numerous changes in brain vessels and the barrier system.