Abstract 18410: The Role of CD40 in Endothelial and Smooth Muscle Cells in Atherosclerosis

Objective: The interaction of CD40-CD40 ligand (CD40L; CD154) plays a central role in inflammatory disease. However, there are conflicting reports about its contribution to atherogenesis. Some of this controversy may arise from cell type-specific signaling initiated by CD40 ligation. To further clarify the cell-specific roles of CD40-associated inflammation in the context of atherosclerosis, we generated tamoxifen-inducible smooth muscle cell (SMC)-specific CD40 (Smmc-Cre + CD40 fl/fl ) and endothelial cell (EC)-specific CD40 deficient mice (Bmx-Cre + CD40 fl/fl ) on an ApoE-deficient background (iSMC-CD40 -/- /Apoe -/- and iEC-CD40 -/- /Apoe -/- , respectively). Methods & Results: All mice (including CD40 fl/fl /Apoe -/- controls) received tamoxifen at 9 weeks and consumed chow diet for additional 20 weeks to induce slow progression of atherosclerosis. Although less leukocytes adhered to the endothelium in iEC-CD40 -/- /ApoE -/- mice as assessed by intravital microscopy, the size of atherosclerotic plaques did not differ compared with respective controls. In contrast, iSMC-CD40 -/- /ApoE -/- mice exhibited decreased atherosclerotic plaque size in the aortic root. iSMC-CD40 -/- /ApoE -/- mice showed a significant increase of circulating granulocytes and monocytes and a shift to more Ly6C low monocytes and regulatory T cells. Notably, iSMC-CD40 -/- /ApoE -/- mice displayed substantial splenomegaly. CD11b + leukocytes in the peritoneum were decreased suggesting impaired capacity of monocytes and granulocytes to migrate. Conclusion: We studied the role of CD40 in non-hematopoietic vascular cells on atherosclerosis: Whereas EC-specific CD40 deficiency does not affect atherogenesis, SMC-specific deletion of CD40 attenuates atherogenesis, likely by impaired infiltration into the arterial wall. However, further mechanistic studies are ongoing to elucidate the SMC-specific role of CD40 on inflammation and atherosclerosis.