Temporal Proteomic Remodeling of Cerebral Arteries in Male Hypertensive Rats.

Abstract

BACKGROUND: Hypertension is a significant risk factor for several neurological disorders, including stroke and dementia, yet the molecular mechanisms underlying these risks remain poorly understood. In this study, we investigated temporal proteomic remodeling of the cerebrovasculature in male spontaneously hypertensive rats and normotensive Wistar-Kyoto controls at 30 and 40 weeks of age, representing the effect of untreated hypertension from early adulthood to midlife. METHODS: Using male 30- and 40-week-old spontaneously hypertensive rats and Wistar-Kyoto rats, we have performed discovery-based proteomics, histological imaging, and RNA-sequencing data analysis. RESULTS: Proteomic analysis displayed a significant age-dependent change in the protein composition of the cerebrovasculature in the spontaneously hypertensive rat model, which is partly mediated via reduced SRF (serum response factor) expression and associated regulon. Pathway analysis revealed a transient upregulation of mitotic (M-phase) proteins at 30 weeks, indicative of maladaptive smooth muscle proliferation. By 40 weeks, the expression of these proteins was normalized; however, ECM (extracellular matrix)-associated proteins diverged substantially. The ECM remodeling was supported by increased media-to-circumference ratio and collagen deposition from histological analysis. CONCLUSIONS: Our findings demonstrate that hypertension drives a temporal shift in cerebrovascular remodeling, transitioning from early maladaptive smooth muscle proliferation to later ECM-driven structural changes. This progression suggests that the pathogenic mechanisms underlying hypertensive vascular injury are dynamic across the life course, with distinct phases that may require different and timely therapeutic approaches to mitigate the risks of neurovascular diseases.