Serum from Stroke Patients with High-Grade Carotid Stenosis Promotes Cyclooxygenase-Dependent Endothelial Dysfunction in Non-ischemic Mice Carotid Arteries

Abstract

Atherosclerosis is responsible for 20% of ischemic strokes, and severe carotid stenosis is associated with a higher incidence of first-ever and recurrent strokes. The release of pro-inflammatory mediators into the blood in severe atherosclerosis may aggravate endothelial dysfunction after stroke contributing to impair disease outcomes. We hypothesize that environments of severe carotid atherosclerotic disease worsen endothelial dysfunction in stroke linked to enhanced risk of further cerebrovascular events. We mounted nonischemic common carotid arteries from 2- to 4-month-old male Oncins France 1 mice in tissue baths for isometric contraction force measurements and exposed them to serum from men with a recent ischemic stroke and different degrees of carotid stenosis: low- or moderate-grade stenosis (LMGS; < 70%) and high-grade stenosis (HGS; ≥ 70%). The results show that serum from stroke patients induced an impairment of acetylcholine relaxations in mice carotid arteries indicative of endothelium dysfunction. This effect was more pronounced after incubation with serum from patients with a recurrent stroke or vascular death within 1 year of follow-up. When patients were stratified according to the degree of stenosis, serum from HGS patients induced more pronounced carotid artery endothelial dysfunction, an effect that was associated with enhanced circulating levels of IL-1β. Mechanistically, endothelial dysfunction was prevented by both nonselective and selective COX blockade. Altogether, the present findings add knowledge on the understanding of the mechanisms involved in the increased risk of stroke in atherosclerosis and suggest that targeting COX in the carotid artery wall may represent a potential novel therapeutic strategy for secondary stroke prevention.