The role of CD40L and VEGF in the modulation of angiogenesis and inflammation

Abstract Recently, there has been growing interest in deciphering the role of angiogenesis in the progression of atherogenesis. Importantly, CD40–CD40L interactions are of significant relevance because of their involvement in both angiogenesis and atherosclerotic development. Previously, we have shown that recombinant soluble CD40 ligand (rsCD40L) stimulates auto-inflammatory CD40L synthesis and reactive oxygen species (ROS) generation in vascular cells. In the current study, we demonstrate that redox-mediated CD40–CD40L interaction can enhance vascular endothelial growth factor (VEGF)-induced angiogenesis, endothelial migration, and actin polymerization processes. Interestingly, the addition of exogenous VEGF leads to cleavage of de novo CD40L produced in endothelial cells following rsCD40L treatment. Using inhibitor and silencing RNA-based experiments, it was observed that VEGF-induced protease, calpain 2, was responsible for the cleavage of de novo CD40L. While our in vivo experiments using a matrigel plug assay indicate a VEGF and CD40L induced enhancement of angiogenesis, our studies also identify a novel mechanism by which VEGF can abrogate CD40L-mediated inflammation. Together, these studies reveal a new pathway by which VEGF–CD40L interactions can regulate the angiogenic and inflammatory process depending on the specific environment.