First name
Azzurra
Last name
Cottarelli
Year of Study
Thesis Title
Fibroblast growth factor binding protein 1 (FGFBP1) contributes in the nestablishment and maintenance of the Blood Brain Barrier
Thesis Abstract
hat regulates the permeability between the blood and the Central Nervous System, allowing the entrance of nutrients and the exit of toxic metabolites. This specialization of the brain microvasculature results from the interaction of the endothelium with other components of the NeuroVascular Unit (NVU): Basement Membrane (BM), pericytes and astrocyte end-feet.
The canonical Wnt/β-catenin pathway regulates BBB initiation and maintenance. Affymetrix analysis demonstrated that, upon Wnt3a stimulation in murine primary ECs isolated from brain (bMEC), one of the most upregulated transcripts is that of Fibroblast Growth Factor Binding Protein 1 (FGFBP1), a cargo protein that, after secretion in the extracellular matrix (ECM), binds the FGF immobilized in the ECM and mobilizes it, protecting it from degradation and presenting it to FGF tyrosine-kinase receptor.
Since Wnt3a stimulation selectively induces FGFBP1 expression in brain ECs, we hypothesized that it could be involved in the process of initiation and/or maturation of the BBB.
We demonstrated in vivo in zebrafish that FGFBP1 knock down by morpholino presents vascular abnormalities in the brain, together with cerebral hemorrhages and impaired permeability. Using an endothelial-specific FGFBP1 knock out murine model, we further demonstrated that inhibition of endothelial FGFBP1 expression affects brain vascular development, causing vascular defects and increased BBB permeability and influencing the number of pericytes and the composition of the BM. Finally, in vitro FGFBP1 absence promoted a “tip-like” phenotype and an increase in the expression of Plvap in bMECs.
In conclusion, our work proposes a novel role for FGFBP1 in the maintenance of the properties of the BBB and in the regulation of the complex intercellular interactions occurring within the NVU.
The canonical Wnt/β-catenin pathway regulates BBB initiation and maintenance. Affymetrix analysis demonstrated that, upon Wnt3a stimulation in murine primary ECs isolated from brain (bMEC), one of the most upregulated transcripts is that of Fibroblast Growth Factor Binding Protein 1 (FGFBP1), a cargo protein that, after secretion in the extracellular matrix (ECM), binds the FGF immobilized in the ECM and mobilizes it, protecting it from degradation and presenting it to FGF tyrosine-kinase receptor.
Since Wnt3a stimulation selectively induces FGFBP1 expression in brain ECs, we hypothesized that it could be involved in the process of initiation and/or maturation of the BBB.
We demonstrated in vivo in zebrafish that FGFBP1 knock down by morpholino presents vascular abnormalities in the brain, together with cerebral hemorrhages and impaired permeability. Using an endothelial-specific FGFBP1 knock out murine model, we further demonstrated that inhibition of endothelial FGFBP1 expression affects brain vascular development, causing vascular defects and increased BBB permeability and influencing the number of pericytes and the composition of the BM. Finally, in vitro FGFBP1 absence promoted a “tip-like” phenotype and an increase in the expression of Plvap in bMECs.
In conclusion, our work proposes a novel role for FGFBP1 in the maintenance of the properties of the BBB and in the regulation of the complex intercellular interactions occurring within the NVU.
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