Vascular and Neural Transcriptomics Reveal Stage-Dependent Pathways to Inflammation and Cognitive Dysfunction in a...

Area of Science:

• Neuroscience
• Vascular Biology
• Aging Research

Background:

• Chronic arterial hypertension contributes to cerebral microvascular dysfunction and elevates dementia risk in aging populations.
• Therapeutic blood pressure reduction alone has limited efficacy in preserving cognitive health, influenced by disease duration and tissue damage.

Purpose of the Study:

• To elucidate the molecular and cellular mechanisms underlying hypertension's impact on the brain over time.
• To investigate the temporospatial progression of hypertensive cerebrovascular pathology.

Main Methods:

• Utilized spontaneously hypertensive stroke-prone rats, examining initial, early chronic, and late chronic hypertension stages in the frontal cortex.
• Employed a multi-modal approach including behavioral tests, histopathology, immunofluorescence, flow cytometry, RNA sequencing, and PET imaging.

Main Results:

• Hypertension induced behavioral deficits linked to frontal cortex function, with stage-dependent responses.
• Early hypertension stages showed microglial activation, immune cell infiltration, blood-brain barrier disruption, and hypermetabolism.
• Later stages exhibited vascular adaptations like angiogenesis and altered gene expression, including upregulated *Igfbp-5*, which inhibits insulin-like growth factor 1 signaling.

Conclusions:

• The study reveals the stage-dependent nature of hypertensive cerebrovascular pathobiology.
• Findings provide a foundation for identifying stage-specific biomarkers and developing novel interventions for hypertension-related cognitive decline and neurodegenerative diseases.