A single-cell RNA sequencing (scRNA-seq) study, published in Neuron, explores how hypertension affects the brain long before cognitive symptoms appear. By examining individual cell types in a mouse model of angiotensin II–induced hypertension, the researchers mapped early molecular changes that emerge well ahead of detectable neurovascular dysfunction.
Hypertension is a known contributor to cognitive decline, yet the earliest events that set this process in motion have been difficult to pinpoint. To address this, the team profiled neocortical brain cells at two key time points: day 3, when blood pressure has only recently begun to rise and behavior appears normal, and day 42, when neurovascular deficits and cognitive impairment become measurable.
What they observed on day 3 suggests that the brain reacts quickly to hypertensive signals.
Endothelial cells showed disrupted transcellular transport pathways and elevated expression of genes related to aging. These alterations were linked directly to angiotensin II signaling rather than sustained hypertension.
Oligodendrocyte progenitor cells became less efficient at enrobing nerve cells in protective myelin sheaths,
Interneurons showed reduced activity and transcriptional changes affecting nerve signal regulation.
Importantly, these changes emerged before sustained blood pressure elevation. This suggests that early molecular disturbances, rather than prolonged stress on blood vessel walls, may start the trajectory toward cognitive dysfunction.
By day 42, the molecular picture had shifted further. The researchers found gene activity patterns consistent with deficits in myelination, altered oligodendrocyte maturation, and impaired nerve signaling. Nerve cells showed evidence of mitochondrial dysfunction, while endothelial cells continued to exhibit pathway disruptions relevant to blood–brain barrier stability and coordinating blood flow with brain activity.
Taken together, the findings show that hypertension affects multiple brain cell types in stages, beginning with subtle but coordinated transcriptional changes. These results highlight several potential early indicators of hypertension-related neurovascular injury, including endothelial transport dysfunction and impaired oligodendrocyte lineage development. These molecular markers may one day support earlier identification of patients at risk of cognitive decline associated with hypertension.
The authors emphasize that their single-cell dataset provides a detailed molecular framework that could guide future mechanistic studies and support efforts to validate early therapeutic targets aimed at protecting cognitive function in individuals with elevated blood pressure.
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