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 vascular injury remains unclear. Platelets are responsible for >95% of soluble CD40L (sCD40L) in the circulation. Clinically, elevated levels of circulating sCD40L are associated with acute coronary syndromes and an increased probability 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 large amounts of platelets are deposited into the injured vessel wall with marked induction of CD40L expression 1 day after carotid injury in a mouse model, and that CD40L-deficient mice had much less leukocyte accumulation 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 surprisingly suggests that CD40L expressed on vascular wall cells but not on hematopoietic cells may require for the pro-atherogenic function of CD40L. This proposal will investigate the role of CD40L in mediating early inflammation after carotid denudation injury in atherosclerosis-prone apoE-/- mice, and explore potential mechanisms involved by addressing the following specific aims. Aim 1 will define the time course of expression of CD40L on circulating platelets and in the injured vessel wall, and evaluate the relative contributions of CD40L expressed on hematopoietic cells versus vascular wall structural cells by bone marrow transplantation. Aim 2 will test the hypothesis that soluble CD40L, especially platelet-derived CD40L, plays a critical role in mediating early inflammatory responses after wire denudation injury of the carotid artery in atherosclerosis-prone apoE-/- mice, in association with platelet activation and platelet-leukocyte aggregation and their recruitment into the injured vessel wall. These studies will characterize the role of both plateletderived and vascular wall cell(s)-derived CD40L in response to arterial injury and elucidate key cellular/molecular mechanisms involved. These mechanistic studies will provide a rational basis for developing new therapeutic strategies to treat patients undergoing percutaneous vascular interventions.