Abstract Background Arterial hypertension is highly prevalent in the elderly population and represents an important risk factor for vascular cognitive impairment and dementia. Chronic hypertension promotes cerebromicrovascular endothelial dysfunction, increased oxidative stress, and impaired neurovascular coupling. Additionally, hypertension contributes to the development of Carotid Artery Stenosis (CAS), further exacerbating cognitive decline. However, the mechanisms underlying these effects remain poorly defined. Recent studies have highlighted sortilin’s involvement in cardiovascular disease and dementia development. Purpose To evaluate the potential role of sortilin in the molecular mechanism linking hypertension and cognitive impairment. Methods We performed immunohistochemical analysis on C57BL/6J mice brain implanted with osmotic minipumps releasing recombinant sortilin protein or vehicle and monitored for blood pressure (BP) levels. In vitro studies were performed on Human Brain Microvascular Endothelial Cells (HBMECs) treated with Angiotensin II (Ang II) and pre-transfected with siRNA against sortilin. We also recruited specimens from 53 hypertensive patients with CAS, stratified for disease severity, who underwent endarterectomy surgery at the University Hospital. Gene expression analysis was performed on RNA isolated from surgically explanted carotid plaques and from plasma samples. Results Compared to the vehicle group, chronic sortilin infusion in mice led to increased arterial BP, elevated brain expression of 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) markers of lipid peroxidation, and increased brain expression of the glial fibrillary acidic protein (GFAP) marker of astrogliosis. Furthermore, chronic sortilin infusion in mice resulted in higher brain expression of the Intercellular Adhesion Molecule 1 (ICAM-1) and a significant reduction of the vascular endothelial-derived adhesion protein (VE-cadherin), the major adhesion protein that controls vascular integrity. Additionally, in an in vitro model of hypertension using HBMECs, sortilin silencing prevented AngII-induced VE-cadherin reduction, suggesting a protective effect against vascular endothelial dysfunction and potential neurovascular unit impairment. Moreover, SORT mRNA expression was significantly elevated in both carotid plaques and plasma from patients with severe CAS compared to those in the mild group, with OSTEOCALCIN mRNA expression showing a parallel increase. Conclusions Our data suggest that sortilin could play a key role in hypertension-induced cognitive impairment, highlighting its potential as a novel therapeutic target.
Abate et al. (Fri,) studied this question.