Integration of spatial and single-cell transcriptomic analysis uncovers cellular and molecular alterations in the hypertensive brain.

Hypertension is a major global health burden, and the central nervous system (CNS) plays a pivotal role in regulating blood pressure. However, the underlying cellular and molecular mechanisms remain incompletely understood. This study aimed to characterize the spatial and single-cell transcriptomic profiles of CNS regions implicated in hypertension. Spatial transcriptomic sequencing and single-cell RNA sequencing were performed on the hypothalamus and medulla oblongata of spontaneously hypertensive rats and normotensive Wistar-Kyoto controls at 4 and 10 weeks of age. Transcriptomic findings were integrated with histological analyses and validated using human brain tissues. Spatial mapping identified previously unrecognized brain regions within the hypothalamus and medulla oblongata that may contribute to the initiation and progression of hypertension. Distinct neuronal subsets, including Ano5+, Oxt+, and Zeb2+ neurons, were characterized, exhibiting potential crosstalk with microglia, astrocytes, and oligodendrocytes. Further integrated analyses revealed a significant upregulation of Eno1 in hypertensive brains, implicating it in neural regulation of blood pressure. Findings in human samples were consistent with the results obtained from rats. This study provides a comprehensive spatial transcriptomic atlas of the hypertensive brain, uncovering multidimensional molecular mechanisms underlying CNS-mediated blood pressure regulation. These results advance our understanding of neurogenic hypertension and may inform future diagnostic and therapeutic strategies.