Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. A disturbed balance between processes of vascular remodeling, including atherogenesis and neovascularization often forms the basis of cardiovascular pathology. We aim to study the role of non-coding RNAs in vascular remodeling. Using www.targetscan.org, we performed a reverse target prediction on two sets of genes involved in vascular remodeling: 197 genes involved in neovascularization on the one hand and 165 genes involved in atherosclerosis on the other. We found enrichment of binding sites for 27 microRNAs (miRNAs) from a single noncoding RNA gene cluster, located on human chromosome 14q32 in the neovascularization gene set. Strikingly, we also found enrichment of eleven 14q32 miRNAs in the atherosclerosis gene set. The 14q32 cluster forms the largest known non-coding RNA gene cluster, containing 54 microRNAs, 41 small nucleolar RNAs (snoRNAs) and 3 long non-coding RNAs (lncRNAs). This cluster is highly conserved, but in mammals only. SnoRNAs from the 14q32 cluster are of the C/D-box subtype and although they clearly have the same structure and sequence motif conservation of other snoRNAs, they have no known RNA targets. The function of these snoRNAs is likely non-canonical and remains to be elucidated. The 14q32 lncRNAs MEG3 and MEG8 (Rian in mice) likely regulate imprinting and transcription of the cluster and are upregulated in activated endothelial cells under hypoxia1. We have previously shown that 14q32 miRNAs are regulated in three different expression patterns during post-ischemic vascular remodeling2. One third of the 14q32 miRNAs was upregulated in murine muscle tissue within 24 hours after induction of ischemia (early responders), one third was upregulated within 72 hours after induction of ischemia (late responders) and one third of the 14q32 miRNAs was not regulated at all after ischemia (non-responders). Similar to the microRNAs, we now show that the 14q32 snoRNAs follow the same three expression patterns after ischemia, namely early responders, late responders and a non-responder. LncRNAs MEG3 and Rian on the other hand were rapidly downregulated after induction of ischemia. Inhibition of 14q32 miRNAs miR-329, miR-487b, miR-494 and miR-495 using Gene Silencing Oligonucleotides (GSOs) increased both arteriogenesis and angiogenesis, leading to a 40% increase in blood flow recovery in a model for hindlimb ischemia in mice. In addition, we could confirm upregulation of multiple target genes after inhibition of 14q32 microRNAs. We then investigated the effects of 14q32 microRNA inhibition on atherosclerosis. When looking at expression patterns of 14q32 “angiomiRs”, we found that specifically miR-494 was abundantly expressed in murine tissues involved in atherosclerosis, including the liver, spleen and carotid arteries. When looking at human carotid artery lesions, we found that miR-494 expression was doubled in vulnerable plaques compared to plaques of a stable phenotype. Again, we used GSOs to inhibit miR-494 in hypercholesterolemic ApoE-/- mice, after placing semi-constrictive collars around both carotid arteries for 28 days to induce atherosclerotic lesion formation. Atherosclerotic lesion formation was significantly reduced in mice treated with GSO-494, while plaque stability was increased, determined by both a decrease in necrotic core size and an increase in plaque collagen content. Furthermore, inhibition of miR-494 resulted in increased cholesterol efflux in vitro. Indeed, in vivo, plasma total cholesterol levels and VLDL fractions were decreased after miR-494 inhibition. These data demonstrate an important role for the 14q32 non-coding RNA cluster in vascular remodeling and cardiovascular pathology. Furthermore, we showed that inhibition of 14q32 miRs has great therapeutic potential in the prevention and treatment of atherosclerotic disease.