Role of cellular senescence in the age‐associated risk of venous thrombosis

Abstract

During normal aging, expression of the tumor‐suppressor gene, p16ink4a, results in cellular senescence in many tissues, including the vasculature. We hypothesize that p16ink4a‐mediated cellular senescence is associated with impaired hemostasis and contributes to a prothrombotic phenotype. In this study, we have used in vivo murine models of vascular injury to examine the role of p16ink4a and cellular senescence in venous thrombosis. Transgenic mice over‐expressing p16ink4a were developed and real‐time PCR data show a 6.5 fold increase in expression of p16ink4a in the saphenous vein/artery bundle. When challenged with an acute ferric chloride injury to the saphenous vein, the p16ink4a transgenic mice have a significantly shorter occlusion time when compared to wild‐type controls. Wild‐type mice show an average occlusion time of 20 minutes versus 13.5 minutes in the p16ink4a transgenic mice. Additional studies have shown that p16ink4a does not alter blood cell populations or venous flow velocity. Currently, we are examining the role of cellular senescence in the response to injury over time. Our results suggest the p16ink4a transgenic mice have a delayed response to injury and are more sensitive to damage induced by ferric chloride. Our studies with the transgenic p16ink4a mice are the beginning to our understanding the role of cellular senescence in the risk of venous thrombosis.NIH support 1R21AG031068‐01.