Abstract 16993: Thrombospondin 1/CD36 Signaling Promotes Vascular Smooth Muscle Cell Proliferation and Contributes to Neointimal Hyperplasia
Dysregulated vascular smooth muscle cell (VSMC) proliferation contributes to neointima formation during pathogenesis of obstructive vascular diseases. The matricellular protein thrombospondin-1 (TSP1) promotes VSMC growth via CD47. CD36, another TSP receptor on VSMC plays important roles in atherosclerosis, but its effect on VSMC proliferation is not known. We now show that a recombinant peptide containing the so-called TSR regions of TSP1 significantly induced mouse VSMC proliferation. TSP1 containing serum had similar effect. TSR peptides are known to bind CD36, but not CD47 and we found that VSMC lacking CD36 did not proliferate in response to TSR. TSR or serum significantly increased cyclin A expression, which is necessary for S-phase transition. Flow cytometry studies of serum stimulated cells demonstrated that cd36 deletion induced S-phase arrest, suggesting that TSP1/CD36 signaling affects cyclin A expression. Using cell cycle progression inhibitors including L-mimosine, aphidicoline or nocodazole, we excluded an effect of TSP/CD36 signaling on cyclin B and D expression. Serum stimulated expression of cyclin dependent kinase inhibitors p21CIP1 and p27kip1 were lower in cd36 null cells compared to wild type. Activity of STAT3, which has been reported to be negatively associated with cyclin A expression in some cells, was constitutively high in cd36 null VSMC and further increased after serum stimulation. To determine the contribution of VSMC CD36 to vascular pathology, apoe/cd36 double null mice and apoe null mice were subjected to guide wire induced carotid arterial injury. Cd36 null mice showed significantly increased carotid artery blood flow (0.702 ± 0.086 ml/min) compared to controls (0.578 ± 0.049 ml/min; p<0.05) after injury. Immunohistochemical staining showed less proliferating cell nuclear antigen positive VSMCs in the neointima of cd36 null mice. Histological examination revealed significantly less neointimal thickening in cd36 null mice. We conclude that engagement of ligands with CD36 contributes to abnormal VSMC proliferation by impacting cyclin A expression via STAT3, thus deletion of CD36 inhibits neointimal thickening after vascular injury.
- © 2012 by American Heart Association, Inc.