Blocking elevated VEGF‐A attenuates non‐vasculature Fragile X syndrome abnormalities

Abstract

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. In exploring abnormalities associated with the syndrome, we have recently demonstrated abnormal vascular density in a FXS mouse model (Galvan and Galvez, ). One of the most prominent regulators of vascular growth is VEGF-A (Vascular Endothelial Growth Factor A), suggesting that FXS is associated with abnormal VEGF-A expression. In addition to its role in vascular regulation, VEGF-A also induces cellular changes such as increasing cell proliferation, and axonal and neurite outgrowth independent of its effects on vasculature. These VEGF-A induced cellular changes are consistent with FXS abnormalities such as increased axonal material, dendritic spine density, and cell proliferation. In support of these findings, the following study demonstrated that FXS mice exhibit increased expression of VEGF-A in brain. These studies suggest that increased VEGF-A expression in FXS is contributing to non-vascular FXS abnormalities. To explore the role of VEGF-A in mediating non-vascular FXS abnormalities, the monoclonal antibody Bevacizumab was used to block free VEGF-A. Bevacizumab treatment was found to decrease FXS Synapsin-1 expression, a presynaptic marker for synapse density, and reduce FXS testicle weight to control levels. Blocking VEGF-A also alleviated FXS abnormalities on novel object recognition, a test of cognitive performance. These findings demonstrate that VEGF-A is elevated in FXS brain and suggest that its expression promotes non-vascular FXS abnormalities. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 14-25, 2017.

Neocortical developmental analysis of vasculature and their growth factors offer new insight into fragile X syndrome abnormalities

“…Consistent with our prior studies in young adults (Galvan and Galvez, ; Belagodu et al, ), the current study found that PND 60 FXS mice had significantly elevated BVD and VEGF‐A expression (Figs. , and d).…”

“…Our prior studies have demonstrated that FXS is associated with adult abnormalities in both vascular density and VEGF‐A expression (Galvan and Galvez, ; Belagodu et al, ). More importantly, we have shown that decreasing VEGF‐A to WT levels can alleviate some FXS abnormalities (Belagodu et al, ). However, FXS is a developmental disorder and there are multiple VEGF proteins and receptors that could mediate FXS abnormalities at these developmental time points.…”

“…Our studies have shown that blocking VEGF‐A decreases adult FXS synapse density in the neocortex and hippocampus to that observed in control mice. Furthermore, our subsequent behavioral analyses using the learning paradigm novel object recognition demonstrated that blocking VEGF‐A also ameliorated adult FXS learning deficits, making them indistinguishable from controls (Belagodu et al, ). These studies demonstrate that in addition to modulating vasculature, increased VEGF‐A expression in adult FXS mice mediates many neuronal and cognitive abnormalities.…”

“…Our recent studies have demonstrated that one of these proteins, down‐stream of mTORC1, that exhibits elevated expression in adult FXS brain is VEGF‐A (Vascular Endothelial Growth Factor A) (Belagodu et al, ). VEGF‐A is one of the most prominent regulators of brain vascular growth and the most likely explanation for our prior observed increased vasculature in adult FXS mice (Galvan and Galvez, ).…”

SHANK1 is differentially expressed during development in CA1 hippocampal neurons and astrocytes

“…To determine SHANK1 expression levels in the astrocyte‐enriched fraction, the sample along with a whole brain control was processed as described in (Belagodu et al, ). Briefly, cellular fractions were lysed and protein concentrations estimated via bicinchonic acid assay (Thermo Scientific).…”