Vascular and neural transcriptomics reveal stage-dependent pathways to inflammation and cognitive dysfunction in a rat model of hypertension

Chronic arterial hypertension causes cerebral microvascular dysfunction and doubles dementia risk in aging. However, cognitive health preservation by therapeutic blood pressure lowering alone is limited and depends on disease duration, the degree of irreversible tissue damage and whether microvascular function can be restored. This study aimed to understand molecular and cellular temporo-spatial pathomechanisms in the course of hypertension. We investigated the effects of initial, early chronic and late chronic hypertension in the frontal brain of rats by applying behavioral tests, histopathology, immunofluorescence, FACS, microvascular/neural tissue RNA sequencing as well as 18F-FDG PET imaging. Chronic hypertension caused frontal brain-specific behavioral deficits. Our results highlight stage-dependent responses to continuous microvascular stress and wounding by hypertension. Early responses included a fast recruitment of activated microglia to the blood vessels, immigration of peripheral immune cells, blood-brain-barrier leakage and an energy-demanding hypermetabolic state. Vascular adaptation mechanisms were observed in later stages and included angiogenesis and vessel wall strengthening by upregulation of cellular adhesion molecules and extracellular matrix. Additionally, we identified late chronic accumulation of Igfbp-5 in the brains of hypertensive rats, which is also a signature of Alzheimer dementia and attenuates protective Igf-1 signaling. Our study advances the knowledge of involved pathomechanisms and highlights the stage-dependent nature of hypertensive pathobiology. This groundwork might be helpful for basic and clinical research to identify stage-dependent markers in the human disease course, investigate stage-dependent interventions besides blood pressure lowering and better understand the relationship between poor vascular health and neurodegenerative diseases. ### Competing Interest Statement The authors have declared no competing interest.