Deletion of 9p21 Non-Coding Cardiovascular Risk Interval in Mice Alters Smad2 Signaling and Promotes Vascular Aneurysm

Background —Vascular aneurysm is an abnormal local dilatation of an artery that can lead to vessel rupture and sudden death. The only treatment involves surgical or endovascular repair or exclusion. There is currently no approved medical therapy for this condition. Recent data established a strong association between genetic variants in the 9p21 chromosomal region in humans and the presence of cardiovascular diseases, including aneurysms. However, the mechanisms linking this 9p21 DNA variant to cardiovascular risk are still unknown. Methods and Results —Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 (chr4Δ70kb/Δ70kb mice) is associated with reduced aortic expression of cyclin-dependent kinase (CDK) inhibitors p19Arf and p15Inkb . Vascular smooth muscle cells from chr4Δ70kb/Δ70kb mice show reduced transforming growth factor (TGF)-β-dependent canonical Smad2 signaling but increased CDK-dependent Smad2 phosphorylation at linker sites, a phenotype previously associated with tumor growth and consistent with the mechanistic link between reduced canonical TGF-β signalling and susceptibility to vascular diseases. We also show that targeted deletion of the 9p21 risk interval promotes susceptibility to aneurysm development and rupture when mice are subjected to a validated model of aneurysm formation. The vascular disease of chr4Δ70kb/Δ70kb mice is prevented by treatment with a CDK inhibitor. Conclusions —The results establish a direct mechanistic link between 9p21 non-coding risk interval and susceptibility to aneurysm, and may have important implications for the understanding and treatment of vascular diseases.