Role of Cd40L signaling in mediating early inflammation after carotid denudation injury in atherosclerosis-prone apoE-deficient mice

The CD40L, a key inflammatory mediator, playa central role in the development of atherosclerosis; however, its role in response to VcJscl~lar injury remains unclear. Platelets are responsible for >95% of soluble CD40L (sCD40L) in the circulaticm.'IClinically, elevated levels of circulating sCD40L are associated with acute coronary syndromes and an incre':!ls€!dprobability of restenosis after angioplasty. Platelet deposition and activation of inflammatory mediators may provide a key stimulus for early inflammatory responses after vascular injury. Our preliminary data show that ilarge amounts of platelets are deposited into the injured vessel wall with marked induction of CD40L expre!s~ion 1 day after carotid injury in a mouse model, and that CD40L-deficient mice had much less leukocyte acc:umiplation in the injured vessel wall 4h after carotid injury compared with wild-type mice. The importance of various cell types as sources of CD40L in vascular disease remains unknown. A recent BMT study surpriBin~ly suggests that CD40L expressed on vascular wall cells but not on hematopoietic cells may require for the prq-atherogenic function of CD40L. This proposal will investigate the role of CD40L in mediating early inflammation after carotid denudation injury in atherosclerosis-prone apoE-I- mice, and explore potential mechanisms invol~(ed by addressing the following specific aims. Aim 1 will define the time course of expression of CD40L on drculating platelets and in the injured vessel wall, and evaluate the relative contributions of CD40L E:!::