Vascular Remodeling in Cardiovascular Disease

The main way of treating symptomatic atherosclerosis is angioplasty with stent placement. This intervention injures the vascular wall, causing endothelial loss, inflammation and intimal hyperplasia (IH), which frequently cause restenosis, a de novo obstruction of the lumen. To prevent this complication, Drug Eluting Stents have been coated with antiproliferative agents. Although they have proven their efficiency, their use is associated with increased early neoatherosclerosis and, although rare long term thrombosis leading to fatal issue. This side effect is in correlation with an impaired endothelial healing due to the lack of specificity of the antiproliferative drugs. So it is of major importance to find new therapeutic targets to prevent restenosis without interfering with a correct reendothelialization. We have previously shown that the invalidation of the kinase activity of phosphoinositide 3-kinase gamma efficiently prevented intimal hyperplasia in mice after arterial injury. Interestingly, immunohistochemical staining strongly suggested that endothelial coverage was increased in mice lacking PI3Kg activity (PI3KgKD, kinase dead) compared to WT controls. PI3Kg is especially known for its inflammatory and immune roles. Yet, no causal link between endothelial healing and immuno-inflammatory processes has been previously reported. We aimed to study the mechanisms by which PI3Kg is involved in endothelial healing. For this purpose, mice were subjected to an endovascular mechanical injury of the carotid artery. Intravenous injection of Evans Blue, allowing the staining of the deendothelialized area, showed a 2 fold increase in reendothelialization rates in PI3Kg KD mice compared with WT, demonstrating a deleterious role of PI3Kg activity upon endothelial healing. Bone marrow transfer experiment showed that this role was attributable to PI3Kg activity in the medullar compartment. A screen at genetic and protein levels showed a PI3Kg dependant increase in the expression and secretion of IP-10 , (IFNg-induced protein 10) in injured carotid arteries, a chemokine previously identified as a possible regulator of endothelial cell proliferation . Moreover, injection of IP-10 neutralizing antibodies accelerates reendothelialization as the same level than observed in absence of PI3Kg activity. Our results demonstrate that PI3Kg invalidation improves endothelial healing through an indirect mechanism involving IP-10 secretion. When added to our previous results, the inhibition of PI3Kg represents a way of preventing complication of arterial angioplasty such as neoatherosclerosis and late stent thrombosis.