Neocortical vasculature abnormalities in the Fragile X mental retardation syndrome

Galvan, Ashley M.; Galvez, Roberto

doi:10.1016/j.brainres.2012.06.056

Cited by 6 publications

(17 citation statements)

References 37 publications

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“…Historically VEGF‐A has been shown to play a prominent role in vascular regulation, with increased expression being synonymous with increased vasculature (Josko et al, ). Consistent with these studies we previously demonstrated vascular abnormalities in V1 of adult FXS mice (Galvan and Galvez, ). However, in addition to its vascular role, recent studies have demonstrated that VEGF‐A can increase axon growth, cell survival and neurite outgrowth, consistent with abnormalities observed in FXS (excessive axonal material, increased neurogenesis, and increased number of immature dendritic spines); suggesting a role for VEGF‐A in mediating non‐vascular FXS abnormalities (Slegtenhorst‐Eegdeman et al, ; Silverman et al, ; Sondell et al, ; Jin et al, ; Pan et al, ; Pan et al, ).…”

Section: Discussionsupporting

confidence: 90%

“…If decreasing VEGF‐A expression decreases vascular density in FXS brain, decreased nutrients and other signaling factors being delivered via the blood stream could mediate some or all of the benefits observed. Interestingly, it should be noted that our prior studies demonstrated increased vasculature in aged FXS brains with only mild increases in adults (Galvan and Galvez, ), the age group examined in this study. The mild increased vasculature observed in adult FXS brains suggests that abnormalities in vascular density alone could not completely account for the extensive FXS neuronal abnormalities observed at this age.…”

Section: Discussionmentioning

confidence: 61%

“…Although the cause for the syndrome [transcriptional silencing of FMR1 , the gene that codes for the Fragile X Mental Retardation Protein (FMRP)] is known (Pieretti et al, ; Verkerk et al, ), our current understanding of the mechanisms mediating the behavioral and anatomical deficits are not understood. In exploring FXS abnormalities, studies in a mouse model of the syndrome have demonstrated increased neocortical blood vasculature (Galvan and Galvez, ). These findings are consistent with reports from FXS patients demonstrating abnormal cerebral blood profusion (Balci et al, ; Kabakus et al, ) and suggest abnormal vascular development in FXS.…”

Section: Introductionmentioning

confidence: 99%

“…These findings suggest that in FXS, an absence of FMRP, resulting in increased mTORC1 phosphorylation, would subsequently phosphorylate HIF1α, resulting in increased VEGF‐A production. This mechanism would further suggest that VEGF‐A expression is elevated and the most likely cause for increased vasculature in FXS (Galvan and Galvez, ).…”

Section: Introductionmentioning

confidence: 99%

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

Belagodu

Zendeli

Slater

et al. 2016

Developmental Neurobiology

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Belagodu

Zendeli

Slater

et al. 2016

Developmental Neurobiology

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“…It is one of the greatest challenges of contemporary society, and is mainly characterized by a reduced quality of life. In general, disability imposes negative consequences for productivity and social relations in the population, causing inconvenience and unnecessary constraints to patients and their families (Vasconcelos, 2004;Galvan and Galvez, 2012).…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of patients suspected of Fragile X Syndrome

Amancio¹,

Melo²,

Vieira³

et al. 2015

Genet. Mol. Res.

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

Belagodu

Fleming

Galvez

2017

Developmental Neurobiology

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Fragile X Syndrome (FXS) is the most common single gene cause for Autism Spectrum Disorder and the most prevalent form of inherited mental retardation. Our prior studies have demonstrated that adult FXS mice have abnormal blood vessel density (BVD) and elevated Vascular Endothelial Growth Factor A expression (VEGF-A). VEGF-A is one of the most prominent regulators of BVD, and its abnormal expression is the most likely cause for FXS BVD abnormalities. We have demonstrated that attenuating elevated VEGF-A expression can ameliorate many non-vascular FXS abnormalities (Belagodu, Zendeli Slater and Galvez: Dev Neurobiol 77 (2017) 14-25), suggesting that abnormal VEGF-A expression is an underlying cause for some FXS abnormalities. However, FXS is a developmental disorder and VEGF-A's potential role in mediating FXS abnormalities during development have never been explored. Furthermore, VEGF-A is one protein in a family of proteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, & PLGF) that activate one of three primary receptors (VEGFR1, VEGFR2, & VEGFR3). Abnormal expression of any of these proteins could hinder proper development. The current study demonstrated that FXS mice do not exhibit normal BVD developmental patterns, resulting in elevated adult expression, most likely due to observed elevated VEGF-A adult expression. Interestingly, all five VEGF family of proteins exhibited altered developmental expression patterns that could cause abnormal development. However, none of the receptors exhibited abnormal adult expression, but did exhibit altered developmental expression. Expanding upon our prior analyses, the current study provides additional interesting insight towards potential developmental mechanisms mediating FXS abnormalities, while offering further sites for age specific therapeutic interventions. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1321-1333, 2017.

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Neocortical vasculature abnormalities in the Fragile X mental retardation syndrome

Cited by 6 publications

References 37 publications

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

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

Molecular analysis of patients suspected of Fragile X Syndrome

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

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