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Disrupted transporter protein expression and cell-specific localization reveal neurovascular unit remodeling in human
Xun Bao1, Yuanyuan Jiang1, Beth Hermes2
1Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
Background:
Current understanding of transporter protein expression and localization within the neurovascular unit (NVU) of the human normal brain cortex and glioblastoma (GBM) remains largely qualitative and lacks cellular resolution. This study aimed to provide a quantitative characterization of transporter protein expression and cell-specific localization in the NVU of normal brain cortex and GBM.
Methods:
Protein expression of major ATP-binding cassette transporters and solute carrier transporters was quantified in microvessels isolated from distinct regions of the human normal brain cortex and GBM using LC-MS/MS-based targeted proteomics. NVU structure and cell-specific transporter localization were visualized and quantitatively assessed by high-resolution confocal immunofluorescence microscopy.
Results:
Targeted proteomics revealed marked alterations in transporter protein abundance in microvessels isolated from both non-enhancing and enhancing regions of GBM, compared with normal brain cortex. ATP-binding cassette (ABC) efflux transporters (ABCB1, ABCG2) were largely preserved. Ion and nutrient transporters (Na+/K+-ATPase, GLUT3, EAAT1, EAAT2, SNAT2) were significantly reduced (ANOVA, P < .05). GLUT1 appeared downregulated while not reaching statistical significance. LAT1 and SNAT3 protein abundance was significantly increased (ANOVA, P < .05). Confocal immunofluorescence microscopy demonstrated a well-organized NVU architecture in normal brain cortex and a markedly disorganized structure in GBM. Quantitative co-localization analyses identified distinct, cell-type specific transporter distribution patterns in the normal NVU, contrasted by diffuse and mislocalized transporter expression in GBM NVU.
Conclusions:
GBM drives profound NVU remodeling at both molecular and structural levels. Disruption of transporter protein expression and cell-specific localization likely contributes to pharmacokinetic heterogeneity, metabolic plasticity, and invasive phenotype of GBM.
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