Abstract 15302: Deficiency of Myeloid Membrane-bound Thrombomodulin Attenuates Vascular Inflammation in Abdominal Aortic Aneurysm

Introduction: Thrombomodulin (TM), a glycoprotein predominantly expressed in endothelial cells, has been well known for its anti-coagulant and anti-inflammatory properties. Paradoxically, we recently found a promoting role of monocytic membrane-bound TM in experimental sepsis. Hypothesis: We assessed the hypothesis that membrane-bound TM may participate in vascular inflammation and the development of abdominal aortic aneurysm (AAA). Methods and Results: Characterization of the CaCl 2 -induced AAA in mice revealed that TM expression was mainly localized in vascular smooth muscle cells (VSMCs) and infiltrating macrophages. To investigate the function of membrane-bound TM in vivo, transgenic mice with myeloid- (LysMcre/TM flox/flox ) and VSMC-specific (SM22-cre tg /TM flox/flox ) TM ablation and their wild type counterparts were generated. In the CaCl 2 -induced AAA model, myeloid TM-deficient mice (n=12) but not VSMC TM-deficient mice (n=8), when compared with their wild-type respective controls (TM flox/flox , SM22-cre tg /TM +/+ ), showed attenuated accumulation of macrophages, reduced production of proinflammatory cytokines and suppressed levels of matrix metalloproteinase-9, thereby preventing progressive aortic dilatation. In vitro TM-deficient macrophages had reduced proinflammatory mediator production, macrophage-endothelial cell adhesion and intracellular oxidative stress (e.g., reactive oxygen species [ROS]) versus TM wild-type macrophages. In addition, deficiency of TM in hyperlipidemic mice (ApoE -/- /LysMcre/TM flox/flox , n=9) conferred protection against angiotensin II-infused AAA, compatible with dramatically diminished aortic ROS production and matrix metalloproteinase activities. Finally, human AAA samples (n=6) showed that TM signals were predominantly localized to infiltrating macrophages, implicating the potential involvement of monocytic membrane-bound TM in human diseases. Conclusion: Membrane-bound TM in macrophages plays a critical role in the development of AAA by enhancing macrophage-endothelial cell adhesion, proinflammatory mediator elaboration and intracellular ROS production.