Abstract
BACKGROUND: Chronic arterial hypertension causes cerebral microvascular dysfunction and increases 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 temporospatial mechanisms of disease in the course of hypertension. METHODS: We investigated the effects of initial, early chronic and late chronic hypertension in the frontal brain of spontaneously hypertensive stroke-prone rats by applying behavioral tests, histopathology, immunofluorescence, fluorescence-activated cell sorting, microvascular/neural tissue RNA sequencing, and (18)F-fluorodeoxyglucose positron emission tomography imaging. RESULTS: Chronic hypertension caused behavioral deficits associated with frontal cortex function. Our results highlight stage-dependent responses to continuous microvascular stress and wounding by hypertension. Early chronic responses included a fast recruitment of activated microglia to the blood vessels, immigration of peripheral immune cells, blood-brain barrier breakdown and an energy-demanding hypermetabolic state. Vascular adaptation mechanisms were observed in later stages and included angiogenesis and upregulation of cellular adhesion molecules and extracellular matrix. Among the top upregulated genes in blood vessels, we identified Igfbp-5, which attenuates protective insulin-like growth factor 1 signaling. CONCLUSIONS: Our study provides new insight into mechanisms underlying hypertensive pathobiology and highlights its stage-dependent nature. This groundwork will 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.