Diminished angiogenic capacity in the hippocampus compared to the cortex indicates regional vulnerability

The hippocampus is one of the first regions affected in various neurodegenerative diseases. In this study, we investigated the vascular factors contributing to its susceptibility, aiming to elucidate the underlying vascular mechanisms. Utilizing publicly available single-cell datasets, we analyzed the differential expression of genes in the endothelial cells and other blood-brain barrier (BBB)-associated cells within the hippocampus and compared them to those in the cortex. The identified hub genes were further validated using naïve mouse and ischemia rat models. We identified differentially expressed genes (DEGs) in endothelial cells, pericytes, and astrocytes in the BBB. Subsequent gene ontology (GO) enrichment analysis and protein-protein interaction (PPI) network analysis identified key hub genes: Kdr, Fn1, Pecam1, Cd34, Cd93, and Emcn that related to angiogenesis. Their differential expression was then experimentally verified using microvessels from mouse and rat brains. In the naïve mouse, compared to the hippocampus, the expression of Fn1 and Pecam1 was significantly higher in cortical microvessels, while Kdr, Cd34, and Cd93 exhibited a clear trend of increased expression. In the rat model of ischemia, we observed an upregulation of angiogenesis-related genes-Kdr, Cd34, and Cd93-within the microvasculature of both the hippocampus and cortex. However, their expression levels were relatively lower in the hippocampus compared to the cortex. These findings suggest that the hippocampus has a reduced angiogenic capacity compared to the cortex, which may contribute to its increased vulnerability to neurological disorders.