Overexpression of the Cell Cycle Inhibitor p16INK4a Promotes a Prothrombotic Phenotype Following Vascular Injury in Mice

Objective—Age-associated cellular senescence is thought to promote vascular dysfunction. p16INK4a is a cell cycle inhibitor that promotes senescence and is upregulated during normal aging. In this study, we examine the contribution of p16INK4a overexpression to venous thrombosis. Methods and Results—Mice overexpressing p16INK4a were studied with 4 different vascular injury models: (1) ferric chloride (FeCl3) and (2) Rose Bengal to induce saphenous vein thrombus formation; (3) FeCl3 and vascular ligation to examine thrombus resolution; and (4) lipopolysaccharide administration to initiate inflammation-induced vascular dysfunction. p16INK4a transgenic mice had accelerated occlusion times (13.1±0.4 minutes) compared with normal controls (19.7±1.1 minutes) in the FeCl3 model and 12.7±2.0 and 18.6±1.9 minutes, respectively in the Rose Bengal model. Moreover, overexpression of p16INK4a delayed thrombus resolution compared with normal controls. In response to lipopolysaccharide treatment, the p16INK4a transgenic...