The molecular consequences of hypertension on the human prefrontal cortex

Thesis

Vascular disorders are important risk factors for cognitive decline and dementia, yet their molecular and cellular impact of these disorders on the human brain and its vasculature remains poorly understood. In this study, a large-scale single-nucleus atlas of the human prefrontal cortex vasculature was generated, comprising 671,162 high-quality nuclei from 43 donors—including both control and hypertensive or diabetic individuals—following strict quality control from an initial cohort of 48 donors. This atlas comprises both parenchymal and vascular compartments, including vascular, glial, neuronal, and immune cell populations, providing a comprehensive architecture of human cortical tissue. Strikingly, hypertension induced substantial transcriptional changes, particularly in vascular cell types (endothelial cells, mural cells, and endothelial-mesenchymal transition cells) and astrocytes. In contrast, no significant transcriptomic changes were observed in diabetes, suggesting that the prefrontal cortex is preferentially vulnerable to hypertension. Among hypertension-affected cell types, endothelial cells, which are key components of the blood-brain barrier (BBB), were the most affected, highlighting their high vulnerability to hypertensive stress. Notably, genes related to cell adhesion, synaptic function, and neuronal guidance were significantly downregulated, suggesting a novel role for traditional ‘neuronal’ genes in maintaining vascular integrity. Their dysregulation in endothelial cells and astrocytes may thus impair the neurovascular unit by affecting BBB integrity and angiogenesis. Many of the downregulated genes have previously been implicated in angiogenesis, and the findings position angiogenesis inhibition as a central mechanism of hypertension-induced neurovascular dysfunction. Cognitive decline associated with hypertension may therefore be a consequence of loss of BBB integrity and perfusion. Whilst hypertension-associated GWAS genes were significantly enriched in vascular cell types, there was minimal overlap between GWAS genes and differentially expressed genes. This suggests that observed transcriptomic changes may reflect secondary consequences of disease or long-term epigenetic changes. This study provides valuable insights into the molecular consequences of hypertension on the human prefrontal cortex.

Authors: Han, H

• DOI: 10.5287/ora-yjv9o98op
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: blood-brain barrier; single-nucleus RNA sequencing; genetics; hypertension; cerebrovascular dementia; neurovascular dysfunction; dementia
• Subjects: Molecular neurobiology; Cerebrovascular disease; Neurosciences; Bioinformatics