Altered Vascular and Angiogenic Transcripts in the Neurogenic Niche in Neuroinflammatory-Type Schizophrenia

Growing evidence indicates that vascular processes, including blood-brain barrier (BBB) function and angiogenesis, may be altered in schizophrenia and related to neuroinflammation. The subependymal zone (SEZ) neurogenic niche shows reduced neurogenesis markers in schizophrenia that are more pronounced with neuroinflammation. Since inflammatory neuropathology is related to increased diapedesis-related transcripts, we hypothesize that endothelial cells would be impacted in this neurogenic niche in schizophrenia.

We measured the expression of four BBB-related mRNAs [claudin-5 (CLDN5), occludin (OCLN), platelet endothelial cell adhesion molecule-1 (PECAM1), and tight junction protein 1 (TJP1)] and five angiogenesis-related mRNAs [angiopoietin 1 (ANGPT1), angiopoietin 2 (ANGPT2), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 1 (VEGFR1), and TEK receptor tyrosine kinase (TEK)] via quantitative polymerase chain reaction, followed by semi-quantitative immunofluorescence for claudin-5 and collagen-IV protein. We estimated proportions of vascular cells by running cellular deconvolution on previous bulk RNA sequencing data.

In high-inflammation schizophrenia, we found increased PECAM1 mRNA, CLDN5 mRNA and claudin-5 protein expression potentially relating to leukocyte trafficking and repair of endothelial tight junctions. The estimated proportion of vascular cells and VEGFA mRNA levels were increased, potentially indicating increased angiogenesis in high-inflammation schizophrenia. Higher VEGFA and CLDN5 mRNA levels were associated with higher expression of markers of immune cell transmigration but lower expression of immature neuron markers, suggesting that vascular dysfunction may impact neurogenesis.

These findings reveal that changes in the BBB and angiogenesis are more severe in high-inflammation schizophrenia and appear to be linked to reduced neurogenesis in the SEZ. This study underscores the importance of inflammation in shaping vascular and neurogenic pathology in schizophrenia, offering potential pathways for future therapeutic exploration.