ENDOTHELIAL-MESENCHYMAL TRANSITION IN HYPERTENSION: THE CONSEQUENCES FOR THE NEUROVASCULAR UNIT

Hypertension (HT) is a well-established risk factor for cognitive decline and dementia through structural and molecular changes to the brain vasculature. snRNA-seq data from hypertensive patients revealed a novel cell population exhibiting endothelial–mesenchymal transition (EndoMT) markers, with significant GWAS enrichment in HT and significant downregulation of specific signalling pathways. We aimed to investigate this novel EndoMT cell type and its potential role in hypertension-driven dementia mechanisms. To validate and characterise this population, we employed hCMEC/D3 and primary HBMVEC cell lines as model systems. Primary HBMVEC and hCMEC/D3 cells were cultured for 14 days in media supplemented with various signalling molecules. Cells were immunostained for mesenchymal marker PDGFRB and endothelial marker CD31 at Days 7 and 14 and quantitatively analysed. Strikingly, cells grown without one specific signalling molecule, a growth factor, demonstrated spontaneous EndoMT differentiation as early as Day 7, showing reduced CD31 expression and perinuclear PDGFRB staining in a subpopulation of cells in both lines (20-30% by Day 14). This finding identifies a critical regulator of EndoMT in brain endothelial cells. Future experiments will co-culture FACS-isolated EndoMT cells and healthy endothelial cells with mNGN2 neurons to assess effects on neuronal firing, viability, and synaptic function. EndoMT has been primarily studied in cardiology and neuro-oncology, but our findings suggest it plays a previously unknown but important role in brain vasculature during hypertension and neurodegeneration. Understanding how this transitional state affects the neurovascular unit may reveal novel therapeutic targets for dementia prevention.

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