In the search for markers and modulators of vascular disease, miRNAs have emerged as potent therapeutic targets. We investigated miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. Utilizing patient material from the Biobank of Karolinska Endarterectomies (BiKE), we profiled miRNA expression in symptomatic versus asymptomatic patients with high-grade carotid artery stenosis. A PCR-based miRNA of plasma, sampled at the carotid lesion site, identified eight deregulated miRNAs (miR-15b, -29c, -30c/d, -150, -191, -210 and -500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser-capture microdissection as well as
in situ
hybridization revealed a distinct localization of miR-210 in the fibrous caps of atherosclerotic lesions and showed reduced miR-210 expression in the unstable fibrous cap. We confirmed that miR-210 directly targets the tumor suppressor gene adenomatous polyposis coli (APC), thereby affecting Wnt signaling and regulating vascular smooth muscle cell survival, as well as differentiation, in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in two rodent models of vascular remodeling and plaque rupture. Modulating miR-210
in vitro
and
in vivo
improved fibrous cap stability with implications for vascular disease. We discovered that an unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring vascular smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic disease.
Additive Benefits of Chondroitin Sulfate and Oriented Tethered Epidermal Growth Factor for Vascular Smooth Muscle Cell Survival
