Blood-Brain Barrier and Immune Cell Transmigration: VEGF Signaling Pathways

The BBB is a selective diffusion barrier that is composed of specialized endothelial cells (ECs) that are linked by tight junctions (TJs) and adherens junctions (AJs). These junction complexes can be remodeled during neuroinflammation to form interendothelial gaps that peripheral immune cells will pass through to enter the central nervous system (CNS). VEGF is elevated in the CNS during neuroinflammatory conditions and is a potent inducer of BBB disruption. VEGF binds to its receptor on brain ECs to initiate intracellular signaling cascades that result in the dynamic reorganization of junction complexes and EC retraction. VEGF induces the phosphorylation of TJ proteins, resulting in their disassembly and/or redistribution from the cell border. Specifically, VEGF promotes endocytosis of Occludin and VE-Cadherin. Additionally, VEGF induces degradation of Occludin by the Ubiquitin-proteasome pathway. VEGF has also been shown to down-regulate the expression of Occludin and Claudin-5, and induce reorganization of F-Actin microfilaments into stress fibers, which increases centripetal tension inside the cell resulting in cell retraction.

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