Inflammatory cell influx and vascular cell proliferation underlie atherosclerotic progression and set the stage for thrombosis, which culminates in myocardial infarction and stroke. While many cell surface molecules and inflammatory mediators have been implicated in this self-perpetuating process, the mechanisms that drive inflammation and proliferation remain incompletely characterized. In recent work, we have found that vascular endothelial cells (ECs) and smooth muscle cells (SMCs) as well as monocytes/macrophages (m?s) locally produce C3a and C5a activation fragments and that these anaphylatoxins interact with upregulated C3a and C5a receptors (C3aR and C5aR) on ECs/SMCs/m?s. Our studies show that amplification of this signal transduction is what drives SMC/m? proliferation and evokes m? inflammatory cytokine production. This insight derived from our studies of immune cell activation which uncovered the previously unrecognized fact that local complement synthesis by interacting dendritic cells (DCs) and T cells is an early event in T cell activation and that the resulting C3a/C5a-C3aR/C5aR interactions play a requisite role in T cell proliferation and effector cytokine production. These studies in immune cells further showed that C3aR/C5aR signaling operates tonically to maintain T cell viability and suppress innate cytokine production. Importantly, our studies in ECs/SMCs/m?s show that C3aR/C5aR signal transduction operates tonically as in immune cells. Our work has shown that the generation of C3a/C5a from locally synthesized complement by ECs/SMCs/m?s, like that from immune cells, is regulated by the cell surface C3/C5 convertase inhibitor DAF, and our studies show that DAF expression is controlled transcriptionally by Kruppel-like factor 4 (KLF4). In work with the Simon group, we have found that C3aR/C5aR signaling is what drives the neointimal response to EC injury. Our preliminary studies show that the mechanism underlying this effect is that amplified C3aR/C5aR signal transduction is essential for growth induction by PDGF and VEGF, factors important in both the EC response to injury and atherogenesis. Importantly, our recent work now implicates C3aR/C5aR signaling contributing to the anti- coagulant state of the vasculature. The central hypothesis of this project is that local complement synthesis and autocrine C3aR/C5aR signaling regulates vascular cell responses to injury, which in turn contributes the development of atherosclerosis and thrombosis. In this proposal, we will: 1) Characterize the role of C3aR/C5aR signaling in vascular inflammation, proliferation, and neointimal formation;2) Establish the importance of autocrine C3aR/C5aR signal transduction in atherothrombosis;and 3) Define the link between suppressed C3aR/C5aR signaling by DAF and the anti-atherogenic/anti-thrombotic effects of KLF4. We believe the studies will provide a new window into processes involved in atherothrombosis and that the insights derived from them will identify important therapeutic targets.
Much is known about the processes that cause atherosclerosis and its occlusive complications that lead to heart attack and stroke. Knowledge of how these processes are controlled, however, is lacking. Our laboratory has uncovered the fact that one of these missing links is a novel cellular pathway that we recently showed is critically involved in regulating immune responses. Its further characterization in vasculature should lead to more effective prevention as well as improved treatment of atherosclerosis, heart attack, and stroke.
|Schmaier, A H (2016) The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost 14:28-39|
|McCullough, Rebecca L; McMullen, Megan R; Das, Dola et al. (2016) Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Mol Immunol 75:122-32|
|Schmaier, Alvin H (2016) Antithrombotic potential of the contact activation pathway. Curr Opin Hematol 23:445-52|
|Schmaier, Alvin H (2015) Medically-induced hemophilia C to treat thrombosis. Thromb Res 136:185-6|
|Strainic, Michael G; Shevach, Ethan M; An, Fengqi et al. (2013) Absence of signaling into CD4âº cells via C3aR and C5aR enables autoinductive TGF-Î²1 signaling and induction of Foxp3âº regulatory T cells. Nat Immunol 14:162-71|