Vascular Endothelial Growth Factors Enhance the Permeability of the Mouse Blood-brain Barrier

Abstract

The blood-brain barrier (BBB) impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS) drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF) on BBB permeability in Kunming (KM) mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse), while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI). Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001). Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI) or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS.

Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice

“…Additionally, its neurovascular protective effects were associated with a reduction of VEGF-MMP-9 expression (Won, et al, 2014). Consistent with this observation, we and others have shown that exogenous application of VEGF can increase BBB permeability (Jiang, et al, 2014, J. Wang, et al, 2015).…”

“…Studies have shown that an increase in VEGF expression and downregulation of NKA activity are associated with the aggravation of brain injury (Jiang, et al, 2014, Yang, et al, 2012). The activity of NKA in brain can be downregulated by phosphorylation of the α subunit at Ser23 by PKC or Ser943 by PKA (Yang, et al, 2012).…”

Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

“…This gives plenty of opportunity to RGL stem cells in the developing dentate gyrus (50,51) to receive similar cues and participate in the BBB via the wrapping of blood vessels. Furthermore, exogenous VEGF has been shown to increase the permeability of the BBB (96,97). So the endogenous release of VEGF from perivascular RGL stem cell processes could participate in the induction of vasculogenesis and facilitate an increase in blood-to-brain signaling.…”

Protection of the Blood–Brain Barrier as a Therapeutic Strategy for Brain Damage

“…Several studies suggested that VEGF enhances BBB permeability. [30][31][32] Increased VEGF expressions were observed after brain damage in experimental animal models [33][34][35] and in patients with brain damage. 8,36,37) Argaw et al 27) focused on astrocytic VEGF-A as a key driver of BBB permeability and confirmed that the inactivation of astrocytic VEGF-A reduced BBB breakdown, lymphocyte infiltration and inflammatory damage in a mouse model of multiple sclerosis (MS).…”